Urea Glucokinase Activators

ABSTRACT

The invention provides a compound of general formula (I) 
     
       
         
         
             
             
         
       
     
     wherein the substituents are defined further in the application, as well as further embodiments hereof described in the attached embodiments. 
     The present invention also provides use of the compounds of the invention for preparation of a medicament for the treatment of various diseases, e.g. for the treatment of type 2 diabetes.

FIELD OF THE INVENTION

This application relates to novel urea glucokinase activators and theiruse in treatment of assorted diseases.

BACKGROUND OF THE INVENTION

Glucokinase (GK) is one of four hexokinases that are found in mammals[Colowick, S. P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press,New York, N.Y., pages 1-48, 1973]. The hexokinases catalyze the firststep in the metabolism of glucose, i.e., the conversion of glucose toglucose-6-phosphate. Glucokinase has a limited cellular distribution,being found principally in pancreatic β-cells and liver parenchymalcells. In addition, GK is a rate-controlling enzyme for glucosemetabolism in these two cell types that are known to play critical rolesin whole-body glucose homeostasis [Chipkin, S. R., Kelly, K. L., andRuderman, N. B. in Joslin's Diabetes (C. R. Khan and G. C. Wier, eds.),Lea and Febiger, Philadelphia, Pa., pages 97-115, 1994]. Theconcentration of glucose at which GK demonstrates half-maximal activityis approximately 8 mM. The other three hexokinases are saturated withglucose at much lower concentrations (<1 mM). Therefore, the flux ofglucose through the GK pathway rises as the concentration of glucose inthe blood increases from fasting (5 mM) to postprandial (≈10-15 mM)levels following a carbohydrate-containing meal [Printz, R. G.,Magnuson, M. A., and Granner, D. K. in Ann. Rev. Nutrition Vol. 13 (R.E. Olson, D. M. Bier, and D. B. McCormick, eds.), Annual Review, Inc.,Palo Alto, Calif., pages 463-496, 1993]. These findings contributed overa decade ago to the hypothesis that GK functions as a glucose sensor inβ-cells and hepatocytes (Meglasson, M. D. and Matschinsky, F. M. Amer.J. Physiol. 246, E1-E13, 1984). In recent years, studies in transgenicanimals have confirmed that GK does indeed play a critical role inwhole-body glucose homeostasis. Animals that do not express GK diewithin days of birth with severe diabetes while animals overexpressingGK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. etal., Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEBJ., 10, 1213-1218, 1996). An increase in glucose exposure is coupledthrough GK in β-cells to increased insulin secretion and in hepatocytesto increased glycogen deposition and perhaps decreased glucoseproduction.

The finding that type II maturity-onset diabetes of the young (MODY-2)is caused by loss of function mutations in the GK gene suggests that GKalso functions as a glucose sensor in humans (Liang, Y., Kesavan, P.,Wang, L. et al., Biochem. J. 309, 167-173, 1995). Additional evidencesupporting an important role for GK in the regulation of glucosemetabolism in humans was provided by the identification of patients thatexpress a mutant form of GK with increased enzymatic activity. Thesepatients exhibit a fasting hypoglycemia associated with aninappropriately elevated level of plasma insulin (Glaser, B., Kesavan,P., Heyman, M. et al., New England J. Med. 338, 226-230, 1998). Whilemutations of the GK gene are not found in the majority of patients withtype 2 diabetes, compounds that activate GK and, thereby, increase thesensitivity of the GK sensor system will still be useful in thetreatment of the hyperglycemia characteristic of all type 2 diabetes.Glucokinase activators will increase the flux of glucose metabolism inβ-cells and hepatocytes, which will be coupled to increased insulinsecretion. Such agents would be useful for treating type II diabetes.Several GK activators are known, see, for example, US 2004/0014968(Hofmann-La Roche Inc.), WO 2003/055482 (Novo Nordisk A/S) and WO2004/002481 (Novo Nordisk A/S). Diabetes is characterised by an impairedglucose metabolism manifesting itself among other things by an elevatedblood glucose level in the diabetic patients. Underlying defects lead toa classification of diabetes into two major groups: Type 1 diabetes, orinsulin demanding diabetes mellitus (IDDM), which arises when patientslack β-cells producing insulin in their pancreatic glands, and type 2diabetes, or non-insulin dependent diabetes mellitus (NIDDM), whichoccurs in patients with an impaired β-cell function besides a range ofother abnormalities.

Type 1 diabetic patients are currently treated with insulin, while themajority of type 2 diabetic patients are treated either withsulphonylureas that stimulate β-cell function or with agents thatenhance the tissue sensitivity of the patients towards insulin or withinsulin. Among the agents applied to enhance tissue sensitivity towardsinsulin metformin is a representative example.

Even though sulphonylureas are widely used in the treatment of NIDDMthis therapy is, in most instances, not satisfactory: In a large numberof NIDDM patients sulphonylureas do not suffice to normalise blood sugarlevels and the patients are, therefore, at high risk for acquiringdiabetic complications. Also, many patients gradually lose the abilityto respond to treatment with sulphonylureas and are thus graduallyforced into insulin treatment. This shift of patients from oralhypoglycaemic agents to insulin therapy is usually ascribed toexhaustion of the β-cells in NIDDM patients.

In normal subjects as well as in diabetic subjects, the liver producesglucose in order to avoid hypoglycemia. This glucose production isderived either from the release of glucose from glycogen stores or fromgluconeogenesis, which is a de novo intracellular synthesis of glucose.In type 2 diabetes, however, the regulation of hepatic glucose output ispoorly controlled and is increased, and may be doubled after anovernight fast. Moreover, in these patients there exists a strongcorrelation between the increased fasting plasma glucose levels and therate of hepatic glucose production. Similarly, hepatic glucoseproduction will be increased in type 1 diabetes, if the disease is notproperly controlled by insulin treatment. Since existing forms oftherapy of diabetes does not lead to sufficient glycaemic control andtherefore are unsatisfactory, there is a great demand for noveltherapeutic approaches. Atherosclerosis, a disease of the arteries, isrecognized to be the leading cause of death in the United States andWestern Europe. The pathological sequence leading to atherosclerosis andocclusive heart disease is well known. The earliest stage in thissequence is the formation of “fatty streaks” in the carotid, coronaryand cerebral arteries and in the aorta. These lesions are yellow incolour due to the presence of lipid deposits found principally withinsmooth-muscle cells and in macrophages of the intima layer of thearteries and aorta. Further, it is postulated that most of thecholesterol found within the fatty streaks, in turn, give rise todevelopment of the “fibrous plaque”, which consists of accumulatedintimal smooth muscle cells laden with lipid and surrounded byextra-cellular lipid, collagen, elastin and proteoglycans. The cellsplus matrix form a fibrous cap that covers a deeper deposit of celldebris and more extracellular lipid. The lipid is primarily free andesterified cholesterol. The fibrous plaque forms slowly, and is likelyin time to become calcified and necrotic, advancing to the “complicatedlesion” which accounts for the arterial occlusion and tendency towardmural thrombosis and arterial muscle spasm that characterize advancedatherosclerosis. Epidemiological evidence has firmly establishedhyperlipidemia as a primary risk factor in causing cardiovasculardisease (CVD) due to atherosclerosis. In recent years, leaders of themedical profession have placed renewed emphasis on lowering plasmacholesterol levels, and low density lipoprotein cholesterol inparticular, as an essential step in prevention of CVD. The upper limitsof “normal” are now known to be significantly lower than heretoforeappreciated. As a result, large segments of Western populations are nowrealized to be at particular high risk. Independent risk factors includeglucose intolerance, left ventricular hypertrophy, hypertension, andbeing of the male sex. Cardiovascular disease is especially prevalentamong diabetic subjects, at least in part because of the existence ofmultiple independent risk factors in this population. Successfultreatment of hyperlipidemia in the general population, and in diabeticsubjects in particular, is therefore of exceptional medical importance.

Hypertension (or high blood pressure) is a condition, which occurs inthe human population as a secondary symptom to various other disorderssuch as renal artery stenosis, pheochromocytoma, or endocrine disorders.However, hypertension is also evidenced in many patients in whom thecausative agent or disorder is unknown. While such “essential”hypertension is often associated with disorders such as obesity,diabetes, and hypertriglyceridemia, the relationship between thesedisorders has not been elucidated. Additionally, many patients displaythe symptoms of high blood pressure in the complete absence of any othersigns of disease or disorder.

It is known that hypertension can directly lead to heart failure, renalfailure, and stroke (brain haemorrhaging). These conditions are capableof causing short-term death in a patient. Hypertension can alsocontribute to the development of atherosclerosis and coronary disease.These conditions gradually weaken a patient and can lead to long-termdeath.

The exact cause of essential hypertension is unknown, though a number offactors are believed to contribute to the onset of the disease. Amongsuch factors are stress, uncontrolled emotions, unregulated hormonerelease (the renin, angiotensin aldosterone system), excessive salt andwater due to kidney malfunction, wall thickening and hypertrophy of thevasculature resulting in constricted blood vessels and genetic factors.

The treatment of essential hypertension has been undertaken bearing theforegoing factors in mind. Thus a broad range of beta-blockers,vasoconstrictors, angiotensin converting enzyme inhibitors and the likehave been developed and marketed as antihypertensives. The treatment ofhypertension utilizing these compounds has proven beneficial in theprevention of short-interval deaths such as heart failure, renalfailure, and brain hemorrhaging. However, the development ofatherosclerosis or heart disease due to hypertension over a long periodof time remains a problem. This implies that although high bloodpressure is being reduced, the underlying cause of essentialhypertension is not responding to this treatment. Hypertension has beenassociated with elevated blood insulin levels, a condition known ashyperinsulinemia. Insulin, a peptide hormone whose primary actions areto promote glucose utilization, protein synthesis and the formation andstorage of neutral lipids, also acts to promote vascular cell growth andincrease renal sodium retention, among other things. These latterfunctions can be accomplished without affecting glucose levels and areknown causes of hypertension. Peripheral vasculature growth, forexample, can cause constriction of peripheral capillaries, while sodiumretention increases blood volume. Thus, the lowering of insulin levelsin hyperinsulinemics can prevent abnormal vascular growth and renalsodium retention caused by high insulin levels and thereby alleviateshypertension.

Cardiac hypertrophy is a significant risk factor in the development ofsudden death, myocardial infarction, and congestive heart failure.Theses cardiac events are due, at least in part, to increasedsusceptibility to myocardial injury after ischemia and reperfusion,which can occur in out-patient as well as perioperative settings. Thereis an unmet medical need to prevent or minimize adverse myocardialperioperative outcomes, particularly perioperative myocardialinfarction. Both non-cardiac and cardiac surgery are associated withsubstantial risks for myocardial infarction or death. Some 7 millionpatients undergoing non-cardiac surgery are considered to be at risk,with incidences of perioperative death and serious cardiac complicationsas high as 20-25% in some series. In addition, of the 400,000 patientsundergoing coronary by-pass surgery annually, perioperative myocardialinfarction is estimated to occur in 5% and death in 1-2%. There iscurrently no drug therapy in this area, which reduces damage to cardiactissue from perioperative myocardial ischemia or enhances cardiacresistance to ischemic episodes. Such a therapy is anticipated to belife-saving and reduce hospitalizations, enhance quality of life andreduce overall health care costs of high risk patients. Obesity is awell-known risk factor for the development of many very common diseasessuch as atherosclerosis, hypertension, and diabetes. The incidence ofobese people and thereby also these diseases is increasing throughoutthe entire industrialised world. Except for exercise, diet and foodrestriction no convincing pharmacological treatment for reducing bodyweight effectively and acceptably currently exists. However, due to itsindirect but important effect as a risk factor in mortal and commondiseases it will be important to find treatment for obesity and/or meansof appetite regulation.

The term obesity implies an excess of adipose tissue. In this contextobesity is best viewed as any degree of excess adiposity that imparts ahealth risk. The cut off between normal and obese individuals can onlybe approximated, but the health risk imparted by the obesity is probablya continuum with increasing adiposity. The Framingham study demonstratedthat a 20% excess over desirable weight clearly imparted a health risk(Mann G V N. Engl. J. Med 291:226, 1974). In the United States aNational Institutes of Health consensus panel on obesity agreed that a20% increase in relative weight or a body mass index (BMI=body weight inkilograms divided by the square of the height in meters) above the 85thpercentile for young adults constitutes a health risk. By the use ofthese criteria 20 to 30 percent of adult men and 30 to 40 percent ofadult women in the United States are obese. (NIH, Ann Intern Med103:147, 1985).

Even mild obesity increases the risk for premature death, diabetes,hypertension, atherosclerosis, gallbladder disease, and certain types ofcancer. In the industrialised western world the prevalence of obesityhas increased significantly in the past few decades. Because of the highprevalence of obesity and its health consequences, its prevention andtreatment should be a high public health priority.

When energy intake exceeds expenditure, the excess calories are storedin adipose tissue, and if this net positive balance is prolonged,obesity results, i.e. there are two components to weight balance, and anabnormality on either side (intake or expenditure) can lead to obesity.The regulation of eating behaviour is incompletely understood. To someextent appetite is controlled by discrete areas in the hypothalamus: afeeding centre in the ventrolateral nucleus of the hypothalamus (VLH)and a satiety centre in the ventromedial hypothalamus (VMH). Thecerebral cortex receives positive signals from the feeding centre thatstimulate eating, and the satiety centre modulates this process bysending inhibitory impulses to the feeding centre. Several regulatoryprocesses may influence these hypothalamic centres. The satiety centremay be activated by the increases in plasma glucose and/or insulin thatfollow a meal. Meal induced gastric distension is another possibleinhibitory factor. Additionally the hypothalamic centres are sensitiveto catecholamines, and beta adrenergic stimulation inhibits eatingbehaviour. Ultimately, the cerebral cortex controls eating behaviour,and impulses from the feeding centre to the cerebral cortex are only oneinput. Psychological, social, and genetic factors also influence foodintake.

At present a variety of techniques are available to effect initialweight loss. Unfortunately, initial weight loss is not an optimaltherapeutic goal. Rather, the problem is that most obese patientseventually regain their weight. An effective means to establish and/orsustain weight loss is the major challenge in the treatment of obesitytoday.

SUMMARY OF THE INVENTION

The invention provides a compound of general formula (I)

wherein the substituents are defined below, as well as furtherembodiments hereof described in the attached embodiments.

The present invention also provides use of the compounds of theinvention for preparation of a medicament for the treatment of variousdiseases, e.g. for the treatment of type 2 diabetes.

DEFINITIONS

In the structural formulas given herein and throughout the presentspecification, the following terms have the indicated meaning:

The term “optionally substituted” as used herein means that the moietywhich is optionally substituted is either unsubstituted or substitutedwith one or more of the substituents specified. When the moiety inquestion is substituted with more than one substituent, the substituentmay be the same or different.

The term “adjacent” as used herein regards the relative positions of twoatoms or variables, these two atoms or variables sharing a bond or onevariable preceding or succeeding the other in a variable specification.By way of example, “atom A adjacent to atom B” means that the two atomsA and B share a bond.

The term “halogen” or “halo” means fluorine, chlorine, bromine oriodine.

The term “perhalomethyl” means trifluoromethyl, trichloromethyl,tribromomethyl, or triiodomethyl.

The use of prefixes of this structure: C_(x-y)-alkyl, C_(x-y)-alkenyl,C_(x-y)-alkynyl, C_(x-y)-cycloalyl orC_(x-y)-cycloalkyl-C_(x-y)-alkenyl- and the like designates radical ofthe designated type having from x to y carbon atoms.

The term “alkyl” as used herein, alone or in combination, refers to astraight or branched chain saturated monovalent hydrocarbon radicalhaving from one to ten carbon atoms, for example C₁₋₈-alkyl orC₁₋₆-alkyl. Typical C₁₋₈-alkyl groups and C₁₋₆-alkyl groups include, butare not limited to e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl,4-methylpentyl, neopentyl, n-pentyl, n-hexyl, 1,2-dimethylpropyl,2,2-dimethylpropyl, 1,2,2-trimethylpropyl and the like. The term“C₁₋₈-alkyl” as used herein also includes secondary C₃₋₈-alkyl andtertiary C₄₋₈-alkyl. The term “C₁₋₆-alkyl” as used herein also includessecondary C₃₋₆-alkyl and tertiary C₄₋₆-alkyl.

The term “alkenyl” as used herein, alone or in combination, refers to astraight or branched chain monovalent hydrocarbon radical containingfrom two to ten carbon atoms and at least one carbon-carbon double bond,for example C₂₋₈-alkenyl or C₂₋₆-alkenyl. Typical C₂₋₈-alkenyl groupsand C₂₋₆-alkenyl groups include, but are not limited to, vinyl,1-propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl, 1-butenyl,2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 2,4-hexadienyl, 5-hexenyl and the like.

The term “alkynyl” as used herein alone or in combination, refers to astraight or branched monovalent hydrocarbon radical containing from twoto ten carbon atoms and at least one triple carbon-carbon bond, forexample C₂₋₈-alkynyl or C₂₋₆-alkynyl. Typical C₂₋₈-alkynyl groups andC₂₋₆-alkynyl groups include, but are not limited to, ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl,5-hexynyl, 2,4-hexadienyl and the like.

The term “cycloalkyl” as used herein, alone or in combination, refers toa saturated mono-, bi-, or tricarbocyclic radical having from three totwelve carbon atoms, for example C₃₋₈-cycloalkyl. TypicalC₃₋₈-cycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,bicyclo[3.2.1]octyl, bicyclo[2.2.1]heptyl, norpinyl, norbonyl, norcaryl,adamantyl and the like.

The term “cycloalkenyl” as used herein, alone or in combination, refersto an non-aromatic unsaturated mono-, bi-, or tricarbocyclic radicalhaving from three to twelve carbon atoms, for example C₃₋₈-cycloalkenyl.Typical C₃₋₈-cycloalkyl groups include, but are not limited tocyclohexene, cycloheptene and cyclopentene, and the like.

The term “heterocyclic” or the term “heterocyclyl” as used herein, aloneor in combination, refers to a saturated mono-, bi-, or tricarbocyclicgroup having three to twelve carbon atoms and one or two additionalheteroatoms or groups selected from nitrogen, oxygen, sulphur, SO orSO₂, for example C₃₋₈-heterocyclyl. Typical C₃₋₈-heterocyclyl groupsinclude, but are not limited to, tetrahydrofuryl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-dioxanyl, 1,3-dioxanyl,piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, and the like. Theterm “heterocycloalkenyl” as used herein, alone or in combination,refers to a non-aromatic unsaturated mono-, bi-, or tricyclic radicalhaving from three to twelve carbon atoms, and one or two additionalheteroatoms or groups selected from nitrogen, oxygen, sulphur, SO orSO₂, for example C₃₋₈-hetereocycloalkenyl. TypicalC₃₋₈-hetreocycloalkenyl groups include, but are not limited totetrahydropyridine, azacycloheptene, 2-pyrroline, 3-pyrroline,2-pyrazoline, imidazoline, 4H-pyran, and the like.

The terms “alkoxy” or “alkyloxy”, which are interchangeable termsherein, as used herein, alone or in combination, refers to themonovalent radical R^(a)O—, where R^(a) is alkyl as defined above, forexample C₁₋₈-alkyl giving C₁₋₈-alkoxy. Typical C₁₋₈-alkoxy groupsinclude, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy,butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxyand the like.

The term “alkenyloxy”, as used herein, alone or in combination, refersto the monovalent radical R^(a)O—, where R^(a) is alkenyl as definedabove, for example C₂₋₈-alkyl giving C₂₋₈-alkenyloxy. TypicalC₂₋₈-alkenyloxy groups include, but are not limited to, vinyloxy,propenyloxy, 2-methyl-propenyloxy, butenyloxy, and the like.

The term “alkenylthio”, as used herein, alone or in combination, refersto the monovalent radical R^(a)S—, where R^(a) is alkenyl as definedabove, for example C₂₋₈-alkyl giving C₂₋₈-alkenylthio. TypicalC₂₋₈-alkenyloxy groups include, but are not limited to, vinylthio,propenylthio, 2-methyl-propenylthio, and the like.

The term “alkylthio” as used herein, alone or in combination, refers toa straight or branched monovalent radical comprising an alkyl group asdescribed above linked through a divalent sulphur atom having its freevalence bond from the sulphur atom, for example C₁₋₆-alkylthio. TypicalC₁₋₆-alkylthio groups include, but are not limited to, methylthio,ethylthio, propylthio, butylthio, pentylthio, hexylthio and the like.

The term “alkoxycarbonyl” as used herein refers to the monovalentradical R^(a)OC(O)—, where R^(a) is alkyl as described above, forexample C₁₋₈-alkoxycarbonyl. Typical C₁₋₈-alkoxycarbonyl groups include,but are not limited to, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,sec-butoxycarbonyl, tertbutoxycarbonyl, 3-methylbutoxycarbonyl,n-hexoxycarbonyl and the like.

The term “aryl” as used herein refers to a carbocyclic aromatic ringradical or to an aromatic ring system radical. Aryl is also intended toinclude the partially hydrogenated derivatives of the carbocyclicsystems.

The term “heteroaryl”, as used herein, alone or in combination, refersto an aromatic ring radical with for instance 5 to 7 member atoms, or toa aromatic ring system radical with for instance from 7 to 18 memberatoms, containing one or more heteroatoms selected from nitrogen,oxygen, or sulphur heteroatoms, wherein N-oxides and sulphur monoxidesand sulphur dioxides are permissible heteroaromatic substitutions; suchas e.g. furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl,pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl,indolyl, and indazolyl, and the like. Heteroaryl is also intended toinclude the partially hydrogenated derivatives of the heterocyclicsystems enumerated below.

Examples of “aryl” and “heteroaryl” includes, but are not limited tophenyl, biphenyl, indene, fluorene, naphthyl (1-naphthyl, 2-naphthyl),anthracene (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophene(2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl,isoxazolyl, thiadiazolyl, oxatriazolyl, thiatriazolyl, quinazolin,fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl,pyrrolyl (1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyrazolyl (1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl), imidazolyl (1-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl(1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl 1,2,3-triazol-5-yl,1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl), oxazolyl (2-oxazolyl,4-oxazolyl, 5-oxazolyl), isooxazolyl (isooxazo-3-yl, isooxazo-4-yl,isooxaz-5-yl), isothiazolyl (isothiazo-3-yl, isothiazo-4-yl,isothiaz-5-yl)thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl(2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl(3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl),isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl(2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl),2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl),3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl),5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl),7-(2,3-dihydro-benzo[b]furanyl)), benzo[b]thiophenyl(benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, benzo[b]thiophen-4-yl,benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl),2,3-dihydro-benzo[b]thiophenyl (2,3-dihydrobenzo[b]thiophen-2-yl,2,3-dihydro-benzo[b]thiophen-3-yl, 2,3-dihydro-benzo[b]thiophen-4-yl,2,3-dihydro-benzo[b]thiophen-5-yl, 2,3-dihydro-benzo[b]thiophen-6-yl,2,3-dihydrobenzo[b]thiophen-7-yl), indolyl (1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole(1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl,7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl,4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,8-benzimidazolyl), benzoxazolyl (2-benzoxazolyl, 3-benzoxazolyl,4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl),benzothiazolyl (2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl,6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl,2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine(5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl,5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl,5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), benzo[1,3]dioxole(2-benzo[1,3]dioxole, 4-benzo[1,3]dioxole, 5-benzo[1,3]dioxole,6-benzo[1,3]dioxole, 7-benzo[1,3]dioxole), purinyl, and tetrazolyl(5-tetrazolyl, N-tetrazolyl).

The present invention also relates to partly or fully saturatedanalogues of the ring systems mentioned above.

When two or more of the above defined terms are used in combination,such as in aryl-alkyl, heteroaryl-alkyl, cycloalkyl-C₁₋₆-alkyl and thelike, it is to be understood that the first mentioned radical is asubstituent on the latter mentioned radical, where the point ofsubstitution, i.e. the point of attachment to another part of themolecule, is on the latter of the radicals, for example

aryl-alkyl-:

cycloalkyl-alkyl-:

aryl-alkoxy-:

The term “fused arylcycloalkyl”, as used herein, refers to an arylgroup, as defined above, fused to a cycloalkyl group, as defined aboveand having the indicated number of carbon atoms, the aryl and cycloalkylgroups having two atoms in common, and wherein the cycloalkyl group isthe point of substitution. Examples of “fused arylcycloalkyl” usedherein include 1-indanyl, 2-indanyl, 1-(1,2,3,4-tetrahydronaphthyl),

and the like.

The term “fused heteroarylcycloalkyl”, as used herein, refers to aheteroaryl group, as defined above, fused to a cycloalkyl group, asdefined above and having the indicated number of carbon atoms, the aryland cycloalkyl groups having two atoms in common, and wherein thecycloalkyl group is the point of substitution. Examples of fusedheteroarylcycloalkyl used herein include6,7-dihydro-5H-cyclopenta[b]pyridine, 5,6,7,8-tetrahydroquinoline,5,6,7,8-tetrahydrisoquinoline, 5,6,7,8-tetrahydroquinazoline and thelike

The term “alkylsulfanyl”, as used herein, refers to the group R^(a)S—,where R^(a) is alkyl as described above.

The term “alkylsulfenyl”, as used herein, refers to the groupR^(a)S(O)—, where R^(a) is alkyl as described above.

The term “alkylsulfonyl”, as used herein, refers to the group R^(a)SO₂—,where R^(a) is alkyl as described above.

The term “alkylsulfamoyl”, as used herein, refers to the groupR^(a)NHSO₂—, where R^(a) is alkyl as described above.

The term “dialkylsulfamoyl”, as used herein, refers to the groupR^(a)R^(b)NSO₂—, where R^(a) and R^(b) are alkyl as described above.

The term “alkylsulfinamoyl”, as used herein, refers to the groupR^(a)NHSO—, where R^(a) is alkyl as described above.

The term “dialkylsulfinamoyl”, as used herein, refers to the groupR^(a)R^(b)NSO—, where R^(a) and R^(b) are alkyl as described above.

The term “alkylamino”, as used herein, refers to the group R^(a)NH—,where R^(a) is alkyl as described above.

The term “acyl”, as used herein, refers to the group R^(a)C(O)—, whereR^(a) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, orheterocyclyl as described above.

The term “heteroaryloxy” as used herein, alone or in combination, refersto the monovalent radical R^(a)O—, where R^(a) is heteroaryl as definedabove.

The term “aryloxycarbonyl”, as used herein, refers to the groupR^(a)—O—C(O)—, where R^(a) is aryl as described above.

The term “acyloxy”, as used herein, refers to the group R^(a)C(O)O—,where R^(a) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, orheterocyclyl as described above.

The term “aryloxy”, as used herein refers to the group R^(a)C(O)O—,where R^(a) is aryl as described above.

The term “aroyloxy”, as used herein, refers to the group R^(a)C(O)O—,where R^(a) is aryl as described above.

The term “heteroaroyloxy”, as used herein, refers to the groupR^(a)C(O)O—, where R^(a) is heteroaryl as described above.

Whenever the terms “alkyl”, “cycloalkyl”, “aryl”, “heteroaryl” or thelike or either of their prefix roots appear in a name of a substituent(e.g. arylalkoxyaryloxy) they shall be interpreted as including thoselimitations given above for “alkyl” and “aryl”.

As used herein, the term “oxo” shall refer to the substituent ═O.

As used herein, the term “mercapto” shall refer to the substituent —SH.

As used herein, the term “carboxy” shall refer to the substituent—C(O)OH.

As used herein, the term “cyano” shall refer to the substituent —CN.

As used herein, the term “nitro” shall refer to the substituent —NO₂.

As used herein, the term “aminosulfonyl” shall refer to the substituent—SO₂NH₂.

As used herein, the term “sulfanyl” shall refer to the substituent —S—.

As used herein, the term “sulfenyl” shall refer to the substituent—S(O)—.

As used herein, the term “sulfonyl” shall refer to the substituent—S(O)₂—.

As used herein, the term “direct bond”, where part of a structuralvariable specification, refers to the direct joining of the substituentsflanking (preceding and succeeding) the variable taken as a “directbond”.

The term “lower”, as used herein, refers to an group having between oneand six carbons, and may be indicated with the prefix C_(x-6)—. Loweralkyl may thus be indicated as C₁₋₆-alkyl, while lower alkylene may beindicated as C₂₋₆-alkylene.

A radical such as C_(x-y)-cycloalkyl-C_(a-b)-alkenyl shall designatethat the radical's point of attachment is in part of the radicalmentioned last.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

As used herein, the term “attached” or “−” (e.g. —C(O)R¹¹ whichindicates the carbonyl attachment point to the scaffold) signifies astable covalent bond.

As used herein, the terms “contain” or “containing” can refer to in-linesubstitutions at any position along the above defined alkyl, alkenyl,alkynyl or cycloalkyl substituents with one or more of any of O, S, SO,SO₂, N, or N-alkyl, including, for example, —CH₂—O—CH₂—, —CH₂—SO₂—CH₂—,—CH₂—NH—CH₃ and so forth.

Certain of the above defined terms may occur more than once in thestructural formulae, and upon such occurrence each term shall be definedindependently of the other.

As used herein, the term “solvate” is a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I)) and a solvent. Such solvents for the purpose of the presentinvention may not interfere with the biological activity of the solute.Solvents may be, by way of example, water, ethanol, or acetic acid.

As used herein, the term “biohydrolyzable ester” is an ester of a drugsubstance (in this invention, a compound of formula (I)) which either a)does not interfere with the biological activity of the parent substancebut confers on that substance advantageous properties in vivo such asduration of action, onset of action, and the like, or b) is biologicallyinactive but is readily converted in vivo by the subject to thebiologically active principle. The advantage is that, for example, thebiohydrolyzable ester is orally absorbed from the gut and istrans-formed to (I) in plasma. Many examples of such are known in theart and include by way of example lower alkyl esters (e.g., C₁₋₄), loweracyloxyalkyl esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters.

As used herein, the term “biohydrolyzable amide” is an amide of a drugsubstance (in this invention, a compound of general formula (I)) whicheither a) does not interfere with the biological activity of the parentsubstance but confers on that substance advantageous properties in vivosuch as duration of action, onset of action, and the like, or b) isbiologically inactive but is readily converted in vivo by the subject tothe biologically active principle. The advantage is that, for example,the biohydrolyzable amide is orally absorbed from the gut and istransformed to (I) in plasma. Many examples of such are known in the artand include by way of example lower alkyl amides, α-amino acid amides,alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

As used herein, the term “prodrug” includes biohydrolyzable amides andbiohydrolyzable esters and also encompasses a) compounds in which thebiohydrolyzable functionality in such a prodrug is encompassed in thecompound of formula (I) and b) compounds which may be oxidized orreduced biologically at a given functional group to yield drugsubstances of formula (I). Examples of these functional groups include,but are not limited to, 1,4-dihydropyridine,N-alkylcarbonyl-1,4-dihydropyridine, 1,4-cyclohexadiene, tert-butyl, andthe like.

The term “pharmacologically effective amount” or shall mean that amountof a drug or pharmaceutical agent that will elicit the biological ormedical response of a tissue, animal or human that is being sought by aresearcher or clinician. This amount can be a therapeutically effectiveamount. The term “therapeutically effective amount” shall mean thatamount of a drug or pharmaceutical agent that will elicit thetherapeutic response of an animal or human that is being sought.

The term “treatment” and “treating” as used herein means the managementand care of a patient for the purpose of combating a disease, disorderor condition. The term is intended to include the full spectrum oftreatments for a given disorder from which the patient is suffering,such as the delaying of the progression of the disease, disorder orcondition, the alleviation or relief of symptoms and complications, theprevention of the disease and/or the cure or elimination of the disease,disorder or condition. The patient to be treated is preferably a mammal,in particular a human being.

The term “pharmaceutically acceptable salt” as used herein includespharmaceutically acceptable acid addition salts, pharmaceuticallyacceptable base addition salts, pharmaceutically acceptable metal salts,ammonium salts, and alkylated ammonium salts. Acid addition saltsinclude salts of inorganic acids as well as organic acids.Representative examples of suitable inorganic acids includehydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, and nitricacids. Representative examples of suitable organic acids include formic,acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic,citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic,oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic,ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic,ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic,EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic,p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates,borates, acetates, benzoates, hydroxynaphthoates, glycerophosphates, andketoglutarates. Further examples of pharmaceutically acceptableinorganic or organic acid addition salts include the pharmaceuticallyacceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which isincorporated herein by reference. Examples of metal salts includelithium, sodium, potassium, magnesium, zinc, and calcium salts. Examplesof amines and organic amines include ammonium, methylamine,dimethylamine, trimethylamine, ethylamine, diethylamine, propylamine,butylamine, tetramethylamine, ethanolamine, diethanolamine,triethanolamine, meglumine, ethylenediamine, choline,N,N′-dibenzylethylenediamine, N-benzylphenylethylamine,N-methyl-D-glucamine, and guanidine. Examples of cationic amino acidsinclude lysine, arginine, and histidine.

The pharmaceutically acceptable salts are prepared by reacting thecompound of formula I with 1 to 4 equivalents of a base such as sodiumhydroxide, sodium methoxide, sodium hydride, potassium t-butoxide,calcium hydroxide, and magnesium hydroxide, in solvents such as ether,THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture ofsolvents may be used. Organic bases such as lysine, arginine,diethanolamine, choline, guandine and their derivatives etc. may also beused. Alternatively, acid addition salts wherever applicable areprepared by treatment with acids such as hydrochloric acid, hydrobromicacid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonicacid, methanesulfonic acid, acetic acid, citric acid, maleic acidsalicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid,succinic acid, benzoic acid, benzenesulfonic acid, and tartaric acid insolvents such as ethyl acetate, ether, alcohols, acetone, THF, dioxaneetc. Mixture of solvents may also be used. The term “combinationtherapy”, “combined”, “in combination with”, and the like, as usedherein refers to the administration of a single pharmaceutical dosageformulation which comprises the glucokinase activator compound of thepresent invention and another active agent(s), as well as administrationof each active agent(s) in its own separate pharmaceutical dosageformulation. Where separate dosage formulations are used, the compoundof the present invention and another active agent(s) can be administeredto the patient at essentially the same time, i.e. concurrently, or atseparate staggered times, i.e. sequentially. When given by differentdosage formulations, the route of administration may be the same ordifferent for each agent. Any route of administration known orcontemplated for the individual agents is acceptable for the practice ofthe present invention.

DESCRIPTION OF THE INVENTION

In an embodiment 1 the invention provides a compound of general formula(I)

wherein R¹ is C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, aryl, heteroaryl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₈-cycloalkyl-C₂₋₆-alkenyl,C₃₋₈-cycloalkyl-C₂₋₆-alkynyl, C₃₋₈-cycloalkenyl-C₁₋₆-alkyl,C₃₋₈-cycloalkenyl-C₂₋₆-alkenyl, C₃₋₈-cycloalkenyl-C₂₋₆-alkynyl,C₃₋₈-heterocyclyl-C₁₋₆-alkyl, C₃₋₈-heterocyclyl-C₂₋₆-alkenyl,C₃₋₈-heterocyclyl-C₂₋₆-alkynyl, C₃₋₈-heterocycloalkenyl-C₁₋₆-alkyl,C₃₋₈-heterocycloalkenyl-C₂₋₆-alkenyl,C₃₋₈-heterocycloalkenyl-C₂₋₆-alkynyl, aryl-C₁₋₆-alkyl,aryl-C₂₋₆-alkenyl, aryl-C₂₋₆-alkynyl, heteroaryl-C₁₋₆-alkyl,heteroaryl-C₂₋₆-alkenyl, heteroaryl-C₂₋₆-alkynyl, (fusedaryl-C₃₋₈-cycloalkyl)-C₁₋₆-alkyl, (fusedaryl-C₃₋₈-cycloalkyl)-C₂₋₆-alkenyl, (fusedaryl-C₃₋₈-cycloalkyl)-C₂₋₆-alkynyl, (fusedheteroaryl-C₃₋₈-cycloalkyl)-C₁₋₆-alkyl, (fusedheteroaryl-C₃₋₈-cycloalkyl)-C₂₋₆-alkenyl or (fusedheteroaryl-C₃₋₈-cycloalkyl-C₂₋₆-alkynyl) each of which is optionallysubstituted with one or more substituents R³, R⁴, R⁵ and R⁶;

R² is C₁₋₈-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₈-alkyl,C₃₋₈-cycloalkenyl, C₃₋₈-heterocyclyl, C₃₋₈-heterocycloalkenyl, fusedaryl-C₃₋₈-cycloalkyl, or fused heteroaryl-C₃₋₈-cycloalkyl, each of whichis optionally substituted with one or more substituents R³⁰, R³¹, R³²and R³³;

R³, R⁴, R⁵, R⁶, R³⁰, R³¹, R³² and R³³ are independently selected fromthe group consisting of

-   -   halogen, nitro, cyano, hydroxy, oxo, carboxy, —CF₃; or    -   —NR¹⁰R¹¹; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,        C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₈-cycloalkyl-C₃₋₆-alkenyl, aryl,        aryl-C₁₋₆-alkyl, aryl-C₂₋₆-alkenyl, heteroaryl-C₁₋₆-alkyl,        heteroaryl-C₂₋₆-alkenyl, heterocyclyl-C₁₋₆-alkyl,        heterocyclyl-C₂₋₆-alkenyl, C₁₋₆-alkoxy, C₃₋₆-alkenyloxy,        C₃₋₈-cycloalkoxy, C₃₋₆-cycloalkyl-C₁₋₆-alkoxy,        C₃₋₈-cycloalkenyl-C₁₋₆-alkoxy, C₃₋₈-heterocyclyl-C₁₋₆-alkoxy,        fused aryl-C₃₋₈-cycloalkenyl-C₁₋₆-alkoxy,        C₃₋₈-cycloalkyl-C₃₋₆-alkenyloxy,        C₃₋₈-cycloalkenyl-C₃₋₆-alkenyloxy,        C₃₋₈-heterocyclyl-C₃₋₆-alkenyloxy, fused        C₃₋₈-cycloalkyl-aryloxy, fused heterocyclyl-aryloxy, fused        aryl-C₃₋₈-cycloalkenyl-C₃₋₆-alkenyloxy, aryl-C₁₋₆-alkoxy,        aryl-C₃₋₆-alkenyloxy, heteroaryl, heteroaryl-C₁₋₆-alkoxy,        heteroaryl-C₃₋₆-alkenyloxy, aryloxy, heteroaryloxy,        C₁₋₆-alkylthio, C₃₋₆-alkenylthio,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio,        C₃₋₈-cycloalkenyl-C₁₋₆-alkylthio,        C₃₋₈-heterocyclyl-C₁₋₆-alkylthio, fused        aryl-C₃₋₈-cycloalkenyl-C₁₋₆-alkylthio,        C₃₋₈-cycloalkyl-C₃₋₆-alkenylthio,        C₃₋₈-cycloalkenyl-C₃₋₆-alkenylthio,        C₃₋₈-heterocyclyl-C₃₋₆-alkenylthio, fused        aryl-C₃₋₈-cycloalkenyl-C₃₋₆-alkenylthio, aryl-C₁₋₆-alkylthio,        aryl-C₃₋₆-alkenylthio, heteroaryl-C₁₋₆-alkylthio,        heteroaryl-C₃₋₆-alkenylthio, arylthio, heteroarylthio        amino-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₁₋₆-alkyl,        di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl, C₁₋₆-alkylsulfamoyl,        di(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylsulfinamoyl or        di(C₁₋₆-alkyl)sulfinamoyl each of which is optionally        substituted with one or more substituents independently selected        from R¹²; or    -   —C(O)—R²⁷, —S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, —S(O)₂—NR¹³R¹⁴,        —C₁₋₆-alkyl-C(O)—NR¹³R¹⁴; or    -   two substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹,        R³² and R³³ attached to the same or adjacent atoms together may        form a radical —O—(CH₂)₁₋₃—O—;

R¹⁰ and R¹¹ independently represent hydrogen, C₁₋₆-alkyl,—C(O)—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl, —C(O)—C₃₋₈-cycloalkyl,carboxy-C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl-C(O)OH, —S(O)₂—C₁₋₆-alkyl, or aryl,each of which is optionally substituted with one or more halogens;

R²⁷ is C₁₋₆-alkyl, C₁₋₆-alkoxy, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,C₃₋₈-cycloalkyl-C₂₋₆-alkenyl, aryl, aryl-C₁₋₆-alkyl, aryloxy-C₁₋₆-alkyl,aryl-C₂₋₆-alkenyl, heteroaryl, C₃₋₈-heterocyclyl, heteroaryl-C₁₋₆-alkyl,C₃₋₈-heterocyclyl-C₁₋₆-alkyl, heteroaryloxy-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, carboxy-C₂₋₆-alkenyl, C₁₋₆-alkoxy-C₁₋₆-alkyl,C₁₋₆-alkoxy-C₂₋₆-alkenyl, C₁₋₆-alkylthio-C₁₋₆-alkyl, R¹⁰HN—C₁₋₆-alkyl,R¹⁰R¹¹—N—C₁₋₆-alkyl, R¹⁰R¹¹—N—C₂₋₆-alkenyl, R¹⁰R¹¹—N—S(O)₂—C₁₋₆-alkyl,R¹⁰R¹¹—N—C(O)—C₁₋₆-alkyl, C₁₋₆-alkyl-C(O)—NH—C₁₋₆-alkyl,aryl-C(O)—NH—C₁₋₆-alkyl, heteroaryl-C(O)—NH—C₁₋₆-alkyl,C₃₋₈-cycloalkyl-C(O)—NH—C₁₋₆-alkyl, C₁₋₆-alkyl-S(O)₂—NH—C₁₋₆-alkyl,aryl-S(O)₂—NH—C₁₋₆-alkyl, heteroaryl-S(O)₂—NH—C₁₋₆-alkyl, orC₃₋₈-cycloalkyl-S(O)₂—NH—C₁₋₆-alkyl, each of which is optionallysubstituted with one or more substituents independently selected fromR¹²;

R¹² is halogen, cyano, hydroxy, —C(O)—O—C₁₋₆-alkyl, carboxy, —CF₃,C₁₋₆-alkyl, aryl, heteroaryl, C₁₋₆-alkoxy, C₂₋₆-alkenyloxy,C₃₋₈-cycloalkyloxy, C₃₋₈-cycloalkenyloxy, C₃₋₈-heterocyclyloxy, aryloxy,heteroaryloxy, aryl-C₁₋₆-alkoxy, aryl-C₁₋₆-alkenyloxy,heteroaryl-C₁₋₆-alkoxy, heteroaryl-C₁₋₆-alkenyloxy,C₃₋₈-cycloalkyl-C₁₋₆-alkoxy, C₃₋₈-cycloalkyl-C₁₋₆-alkenyloxy,C₃₋₈-heterocyclyl-C₁₋₆-alkoxy, C₃₋₈-heterocyclyl-C₁₋₆-alkenyloxy, fusedaryl-C₃₋₈-cycloalkyl-C₁₋₆-alkoxy, fusedaryl-C₃₋₈-cycloalkyl-C₁₋₆-alkenyloxy, C₁₋₆-alkylthio, C₂₋₆-alkenylthio,C₃₋₈-cycloalkylthio, C₃₋₈-cycloalkenylthio, C₃₋₈-heterocyclylthio,arylthio, heteroarylthio, aryl-C₁₋₆-alkylthio, aryl-C₁₋₆-alkenylthio,heteroaryl-C₁₋₆-alkylthio, heteroaryl-C₁₋₆-alkenylthio,C₃₋₈-cycloalkyl-C₁₋₆-alkylthio, C₃₋₈-cycloalkyl-C₁₋₆-alkenylthio,C₃₋₈-heterocyclyl-C₁₋₆-alkylthio, C₃₋₈-heterocyclyl-C₁₋₆-alkenylthio,fused aryl-C₃₋₈-cycloalkyl-C₁₋₆-alkylthio, fusedaryl-C₃₋₈-cycloalkyl-C₁₋₆-alkenylthio, —NR¹⁰R¹¹, —S(O)₂CH₃, —S(O)₂CF₃ or—S(O)₂NH₂ each of which is optionally substituted with one or moresubstituents independently selected from R³⁸;

R¹³ and R¹⁴ are independently selected from the group consisting ofhydrogen, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, aryl, orheteroaryl, each of which is optionally substituted with one or moresubstituents independently selected from R¹⁵; or R¹³ and R¹⁴ togetherwith the nitrogen to which they are attached form a 3 to 8 memberedheterocyclic ring with the said nitrogen atom, the heterocyclic ringoptionally containing one or two further heteroatoms selected fromnitrogen, oxygen and sulphur;

R¹⁵ is halogen, cyano, hydroxy, carboxy, —CF₃, C₁₋₆-alkyl, —S(O)₂CH₃, or—S(O)₂NH₂;

R³⁸ is halogen or C₁₋₆-alkyl;

A is heteroaryl which is substituted with at least one substituentindependently selected from R⁷, R⁸ and R⁹; wherein

-   -   R⁷, R⁸ and R⁹ are independently selected from        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,            C₃₋₆-cycloalkylthio, C₁₋₆-alkylamino, C₁₋₆-alkylsulfanyl,            —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl, —NH—C(O)—C₁₋₆-alkyl,            —C₁₋₆-alkoxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-S—C₁₋₆-alkyl or            hydroxy-C₁₋₆-alkyl, each of which is substituted with one or            more substituents independently selected from R³⁴; or        -   —C₁₋₆-alkyl-NR¹⁹R²⁰, —C₂₋₆-alkenyl-NR¹⁹R²⁰,            —C₁₋₆-alkyl-S—R²¹, —C₁₋₆-alkyl-S(O)—R²¹,            —C₁₋₆-alkyl-S(O)₂—R²¹, —S(O)₂—R²¹,            —S(O)₂—N(R¹⁹)(C₁₋₆-alkyl)-C(O)—NR²²R²³ or —S(O)₂—NR¹⁹R²⁰,            each of which is substituted with one or more substituents            independently selected from R²⁵; or        -   —C(O)NR²²R²³, —C₁₋₆-alkyl-C(O)NR²²R²³ each of which is            substituted with one or more substituents independently            selected from R²⁵; or two of R⁷, R⁸ and R⁹ can be taken            together to form a C₂₋₅-alkylene bridge; the C₂₋₅-alkylene            bridge is optionally substituted with one or more            substituents independently selected from R¹⁶; or        -   carboxy, nitro, hydroxy, —SCN; or        -   C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkenyloxy,            C₂₋₆-alkenylthio, C₃₋₆-cycloalkyl,            C₃₋₆-cycloalkyl-C₁₋₆-alkyl, C₃₋₆-cycloalkoxy,            C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, —C(O)—O—C₁₋₆-alkyl, formyl,            —C(O)—C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,            carboxy-C₁₋₆-alkyl each of which is optionally substituted            with one or more substituents independently selected from            R¹⁶; or        -   heteroaryl, heteroaryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkoxy,            heteroaryl-C₁₋₆-alkylthio, heteroaryl-thio-C₁₋₆-alkyl,            heteroaryl-oxy-C₁₋₆-alkyl, heteroaryloxy, heteroarylthio,            —C(O)-aryl, or —C(O)-heteroaryl, each of which is optionally            substituted on the aryl or heteroaryl part with one or more            substituents independently selected from R¹⁷; or        -   C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkylthio,            C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₈-cycloalkenyl-C₁₋₆-alkyl,            C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, C₃₋₆-cycloalkyl-C₁₋₆-alkylthio,            each of which is optionally substituted on the cycloalkyl            part with one or more substituents independently selected            from R¹⁸; or        -   C₃₋₈-heterocyclyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl,            C₃₋₈-heterocyclyl-C₁₋₆-alkylthio, C₃₋₈-heterocyclylthio,            C₃₋₈-heterocyclyl-amino-C₁₋₆-alkyl, or            —C(O)—C₃₋₈-heterocyclyl, each of which is optionally            substituted with one or more substituents independently            selected from R¹⁶; or        -   —C₁₋₆-alkyl-NR³⁶R³⁷, —C₂₋₆-alkenyl-NR³⁶R³⁷ or            —S(O)₂—NR³⁶R³⁷, each optionally substituted with one or more            substituents independently selected from R²⁵; or            —C(O)NR³⁶R³⁷,            —C₁₋₆-alkyl-C(O)NR³⁶R³⁷—C₁₋₆-alkyl-NH—NR²²R²³—C₁₆-alkyl-NH—C(O)—C₁₆-alkyl-NR²²R²³,            each optionally substituted with one or more substituents            independently selected from R²⁶;

If more than one substituent R⁷, R⁸ and R⁹ is present on A thatadditional R⁷, R⁸ and R⁹ may be selected from halogen or C₁₋₆-alkyl;

R¹⁶, R¹⁷, and R¹⁸ are independently C₁₋₆-alkyl, halogen, nitro, cyano,hydroxy, carboxy, oxo, —CF₃, carboxy-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—NR¹⁹R²⁰,—C(O)—O—C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl-C(O)—C₁₋₆-alkyl, —NR¹⁹R²⁰,—NHS(O)₂C₁₋₆-alkyl, —NHS(O)₂CF₃, —C(O)NR¹⁹R²⁰, —S(O)₂C₁₋₆-alkyl,—S(O)₂CF₃, —S(O)₂CH₂CF₃ or —S(O)₂NR¹⁹R²⁰;

R³⁴ is halogen, nitro, cyano, hydroxy, carboxy, —CF₃; or

carboxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl or—C(O)—C₁₋₆-alkyl-C(O)—C₁₋₆-alkyl each optionally substituted with one ormore halogens;

R¹⁹ and R²⁰ independently represent hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl,hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, aryl, heteroaryl,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₈-heterocyclyl,aryl-C₁₋₆-alkyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-NR²²R²³, or—S(O)₂—C₁₋₆-alkyl, each of which is optionally substituted with one ormore substituents independently selected from R²⁴, or R¹⁹ and R²⁰together with the nitrogen to which they are attached form a 3 to 8membered heterocyclic ring with the said nitrogen atom, the heterocyclicring optionally containing one or two further heteroatoms selected fromnitrogen, oxygen and sulphur, the heterocyclic ring is optionallysubstituted with one or more substituents independently selected fromR²⁴;

R²¹ is selected from

-   -   C₁₋₆-alkyl, C₂₋₆-alkenyl, carboxy-C₁₋₆-alkyl,        C₁₋₆-alkylamino-C₁₋₆-alkyl or hydroxy-C₁₋₆-alkyl,        —C₁₋₆-alkyl-NR²²R²³; or    -   aryl, heteroaryl, aryl-C₁₋₆-alkyl, or heteroaryl-C₁₋₆-alkyl,        wherein the aryl or heteroaryl part is optionally substituted        with one or more substituents independently selected from R²⁴;        or    -   C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,        C₃₋₈-cycloalkenyl-C₁₋₆-alkyl;

R²² and R²³ are independently selected from hydrogen, C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl,—C₁₋₆-alkyl-S(O)₂—C₁₋₆-alkyl, —C₁₋₆-alkyl-S(O)₃H, C₃₋₈-cycloalkyl, aryl,or heteroaryl; or R²² and R²³ together with the nitrogen to which theyare attached form a 3 to 8 membered heterocyclic ring with the saidnitrogen atom, the heterocyclic ring optionally containing one or twofurther heteroatoms selected from nitrogen, oxygen and sulphur, theheterocyclic ring is optionally substituted with one or moresubstituents independently selected from R²⁴;

R³⁶ and R³⁷ are independently selected from carboxy-C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl,—C₁₋₆-alkyl-S(O)₂—C₁₋₆-alkyl, C₃₋₈-cycloalkyl, aryl, or heteroaryl; orR³⁶ and R³⁷ together with the nitrogen to which they are attached form a3 to 8 membered heterocyclic ring with the said nitrogen atom, theheterocyclic ring optionally containing one or two further heteroatomsselected from nitrogen, oxygen and sulphur, the heterocyclic ring isoptionally substituted with one or more substituents independentlyselected from R²⁴;

R²⁴ is halogen, nitro, cyano, hydroxy, carboxy, oxo, —CF₃, C₁₋₆-alkyl,hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl,—C(O)—C₃₋₈-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)—C₃₋₈-heterocyclyl —C(O)—O—C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, aryl, heteroaryl, aryl-C₁₋₆-alkyl,heteroaryl-C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—C₃₋₈-heterocyclyl, —C(O)—O—C₁₋₆-alkyl-aryl,—NH—S(O)₂R²⁸, or —S(O)₂R²⁸, wherein each cyclic moiety is optionallysubstituted with one or more substituents independently selected fromR²⁹;

R²⁵ and R²⁶ are independently C₁₋₆-alkyl, halogen, nitro, cyano,hydroxy, —C(O)—O—C₁₋₆-alkyl, carboxy, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, carboxy-C₃₋₈-cycloalkyl, —CF₃, —S(O)₂CH₃, or—S(O)₂NH₂;

R²⁸ is C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,C₃₋₈-cycloalkyl, aryl, aryl-C₁₋₆-alkyl, heteroaryl optionallysubstituted with C₁₋₆-alkyl, —NH₂, or —N(CH₃)₂;

R²⁹ is halogen, nitro, cyano, hydroxy, carboxy, oxo, —CF₃, C₁₋₆-alkyl,or C₁₋₆-alkoxy;

R³⁵ is halogen, nitro, cyano, hydroxy, —C(O)—O—C₁₋₆-alkyl, carboxy,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —CF₃, —S(O)₂CH₃, or—S(O)₂NH₂;

as well as any salt hereof with a pharmaceutically acceptable acid orbase, or any optical isomer or mixture of optical isomers, including aracemic mixture, or any tautomeric forms.

Embodiment 2. A compound according to embodiment 1 wherein R¹ isC₁₋₈-alkyl, C₂₋₈-alkenyl, aryl, heteroaryl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,C₃₋₈-cycloalkyl-C₂₋₆-alkenyl, C₃₋₈-cycloalkenyl-C₁₋₆-alkyl,C₃₋₈-cycloalkenyl-C₂₋₆-alkenyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl,C₃₋₈-heterocyclyl-C₂₋₆-alkenyl, C₃₋₈-heterocycloalkenyl-C₁₋₆-alkyl,C₃₋₈-heterocycloalkenyl-C₂₋₆-alkenyl, aryl-C₁₋₆-alkyl, oraryl-C₂₋₆-alkenyl, each of which is optionally substituted with one ormore substituents R³, R⁴, R⁵ and R⁶.

Embodiment 3. A compound according to embodiment 2 wherein R¹ isC₁₋₈-alkyl, C₂₋₈-alkenyl, aryl, heteroaryl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,C₃₋₈-cycloalkyl-C₂₋₆-alkenyl, C₃₋₈-cycloalkenyl-C₁₋₆-alkyl,C₃₋₈-cycloalkenyl-C₂₋₆-alkenyl, aryl-C₁₋₆-alkyl, or aryl-C₂₋₆-alkenyl,each of which is optionally substituted with one or more substituentsR³, R⁴, R⁵ and R⁶.

Embodiment 4. A compound according to embodiment 3 wherein R¹ isC₁₋₈-alkyl, C₂₋₈-alkenyl, aryl, heteroaryl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,C₃₋₈-cycloalkenyl-C₁₋₆-alkyl, or aryl-C₁₋₆-alkyl, each of which isoptionally substituted with one or more substituents R³, R⁴, R⁵ and R⁶.

Embodiment 5. A compound according to embodiment 4 wherein R¹ isC₁₋₈-alkyl, C₂₋₈-alkenyl, phenyl, pyridinyl, benzo[1,3]dioxolyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₈-cycloalkenyl-C₁₋₆-alkyl, orphenyl-C₁₋₆-alkyl, each of which is optionally substituted with one ormore substituents R³, R⁴, R⁵ and R⁶.

Embodiment 6. A compound according to embodiment 5 wherein R¹ is methyl,ethyl, propyl, butyl, 3-methyl-butyl, 2,2-dimethylpropyl,1,3,-dimethylbutyl, isopropyl, 3-methyl-but-2-enyl, ethenyl, propenyl,butenyl, cyclopropyl-methyl, cyclopropyl-ethyl, cyclopropyl-propyl,cyclobutyl-methyl, cyclobutyl-ethyl, cyclobutyl-propyl,cyclopentyl-methyl, cyclopentyl-ethyl, cyclopentyl-propyl,cyclohexyl-methyl, cyclohexyl-ethyl, cyclohexyl-propyl,cycloheptyl-methyl, cycloheptyl-ethyl, cycloheptyl-propyl,cyclohexenyl-methyl, cyclohexenyl-ethyl, cyclohexenyl-propyl,cycloheptenyl-methyl, cycloheptenyl-ethyl, cycloheptenyl-propyl, phenyl,pyridinyl, benzo[1,3]dioxolyl, benzyl, phenethyl, phenyl-propyl,bicyclo[2.2.1]heptenyl-methyl or bicyclo[2.2.1]heptyl-methyl, each ofwhich is optionally substituted with one or more sub-stituents R³, R⁴,R⁵ and R⁶.

Embodiment 7. A compound according to embodiment 6 wherein R¹ is methyl,ethyl, propyl, butyl, 3-methyl-butyl, 2,2-dimethylpropyl,1,3,-dimethylbutyl, isopropyl, 3-methyl-but-2-enyl, ethenyl,cyclohexyl-methyl, cyclohexyl-ethyl, cyclohexyl-propyl,cyclohexenyl-methyl, cyclohexenyl-ethyl, cyclohexenyl-propyl,cycloheptenyl-methyl, cycloheptenyl-ethyl, phenyl, pyridinyl,benzo[1,3]dioxolyl, benzyl, phenethyl, phenylpropyl,bicyclo[2.2.1]heptenyl-methyl or bicyclo[2.2.1]heptyl-methyl, each ofwhich is optionally substituted with one or more substituents R³, R⁴, R⁵and R⁶.

Embodiment 8. A compound according to embodiment 7 wherein R¹ is methyl,ethyl, propyl, isopropyl, butyl or 3-methyl-butyl, each of which isoptionally substituted with one or more substituents R³, R⁴, R⁵ and R⁶.

Embodiment 9. A compound according to embodiment 7 wherein R¹ is benzyl,phenethyl or phenylpropyl, optionally substituted with one or moresubstituents R³, R⁴, R⁵ and R⁶.

Embodiment 10. A compound according to embodiment 7 wherein R¹ isphenyl, optionally substituted with one or more substituents R³, R⁴, R⁵and R⁶.

Embodiment 11. A compound according to any one of the embodiments 1 to10 wherein R² is C₁₋₈-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₈-alkylor C₃₋₈-cycloalkenyl, each of which is optionally substituted with oneor more substituents R³⁰, R³¹, R³² and R³³.

Embodiment 12. A compound according to embodiment 11 wherein R² isC₃₋₈-cycloalkyl or C₃₋₈-cycloalkyl-C₁₋₈-alkyl optionally substitutedwith one or more substituents R³⁰, R³¹, R³² and R³³.

Embodiment 13. A compound according to embodiment 12 wherein R² isC₃₋₈-cycloalkyl optionally substituted with one or more substituentsR³⁰, R³¹, R³² and R³³.

Embodiment 14. A compound according to embodiment 11 wherein R² ismethyl, ethyl, propyl, butyl, pentyl, hexyl, 3-methylbutyl,3,3-dimethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl,methylcyclohexyl, or ethylcyclopentyl, each of which may optionally besubstituted with R³⁰.

Embodiment 15. A compound according to embodiment 14 wherein R² ismethylcyclopentyl or methylcyclohexyl, each of which may optionally besubstituted with R³⁰.

Embodiment 16. A compound according to embodiment 14 wherein R² iscyclohexyl optionally substituted with R³⁰.

Embodiment 17. A compound according to any one of the embodiments 1 to16 which is

wherein A and R³⁰ are as defined in embodiment 1.

Embodiment 18. A compound according to any one of the embodiments 1 to16 which is

wherein A, R³ and R³⁰ are as defined in embodiment 1.

Embodiment 19. A compound according to any one of the embodiments 1 to16 which is

wherein A, R³, R⁴, R⁵ and R³⁰ are as defined in embodiment 1.

Embodiment 20. A compound according to any one of the embodiments 1 to19 wherein R³, R⁴, R⁵ and R⁶ are independently selected from the groupconsisting of

-   -   halogen, hydroxy, carboxy, —CF₃; or    -   —NR¹⁰R¹¹; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₁₋₆-alkoxy, C₃₋₆-alkenyloxy,        C₃₋₈-cycloalkyl, C₃₋₈-cycloalkoxy, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, C₃₋₈-cycloalkenyl-C₁₋₆-alkoxy,        phenyl-C₁₋₆-alkoxy, each of which is optionally substituted with        one or more substituents independently selected from R¹²; or    -   Phenyl, phenoxy, benzyloxy, indanyloxy, benzo[1,3]dioxolyloxy,        phenylthio, or benzylthio; or    -   —C(O)—R²⁷, —S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, or —S(O)₂—NR¹³R¹⁴; or    -   two substituents selected from R³, R⁴, R⁵ and R⁶ attached to the        same or adjacent atoms together may form a radical        —O—(CH₂)₁₋₃—O—.

Embodiment 21. A compound according to embodiment 20 wherein R³, R⁴, R⁵and R⁶, are independently selected from the group consisting of

halogen, —CF₃, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₁₋₆-alkoxy, phenyl, phenoxy,benzyloxy, indanyloxy, benzo[1,3]dioxolyloxy, phenylthio, benzylthio,phenyl-C₁₋₆-alkoxy, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkoxy, orC₃₋₆-cycloalkyl-C₁₋₆-alkoxy, each of which is optionally substitutedwith one or more substituents independently selected from R¹²; or—NR¹⁰R¹¹, —C(O)—R²⁷, —S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, or —S(O)₂—NR¹³R¹⁴.

Embodiment 22. A compound according to embodiment 21 wherein R³, R⁴, R⁵and R⁶ are independently selected from the group consisting of halogen,CF₃, C₁₋₆-alkyl, C₁₋₆-alkoxy, phenoxy, benzyloxy, phenylthio,benzylthio, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkoxy, orC₃₋₆-cycloalkyl-C₁₋₆-alkoxy, each of which is optionally substitutedwith one or more substituents independently selected from R¹²; or—NR¹⁰R¹¹, —C(O)—R²⁷, —S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, or —S(O)₂—NR¹³R¹⁴.

Embodiment 23. A compound according to embodiment 21 wherein R³, R⁴, R⁵and R⁶ are independently selected from the group consisting of F, Cl,Br, —CF₃, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, ethenyl,propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,phenyl, methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy,tert-butoxy, cyclohexyloxy, phenoxy, benzyloxy, indanyloxy,benzo[1,3]dioxolyloxy, cyclopropyl-methoxy, cyclopropyl-ethoxy,cyclopropyl-propoxy, cyclobutyl-methoxy, cyclobutyl-ethoxy,cyclobutyl-propoxy, cyclopentyl-methoxy, cyclopentyl-ethoxy,cyclopentyl-propoxy, cyclohexyl-methoxy, cyclohexyl-ethoxy,cyclohexyl-propoxy, cycloheptyl-methoxy, cycloheptyl-ethoxy,cycloheptyl-propoxy, phenylethoxy, phenylthio or benzylthio, each ofwhich is optionally substituted with one or more substituentsindependently selected from R¹²; or —NR¹⁰R¹¹, —C(O)—R²⁷, —S(O)₂—R⁷,—C(O)—NR¹³R¹⁴, or —S(O)₂—NR¹³R¹⁴.

Embodiment 24. A compound according to embodiment 23 wherein R³, R⁴, R⁵and R⁶ are independently selected from the group consisting of F, Cl,Br, —CF₃, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, butoxy,isopropoxy, isobutoxy, tert-butoxy, cyclohexyloxy, phenoxy, benzyloxy,indanyloxy, benzo[1,3]dioxolyloxy, phenylmethoxy, phenylethoxy,phenylthio or benzylthio, each of which is optionally substituted withone or more substituents independently selected from R¹²; or —NR¹⁰R¹¹,—C(O)—R²⁷, —S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, or —S(O)₂—NR¹³R¹⁴.

Embodiment 25. A compound according to embodiment 24 wherein R³, R⁴, R⁵and R⁶ are independently selected from the group consisting of F, Cl,Br, —CF₃, methyl, methoxy, ethoxy, propoxy, butoxy, phenoxy, benzyloxy,phenylthio or benzylthio, each of which is optionally substituted withone or more substituents independently selected from R¹².

Embodiment 26. A compound according to embodiment 25 wherein R³, R⁴, R⁵and R⁶ are independently selected from the group consisting of phenoxyand benzyloxy, each of which is optionally substituted with one or moresubstituents independently selected from R¹².

Embodiment 27. A compound according to embodiment 25 wherein R³, R⁴, R⁵and R⁶ are independently selected from the group consisting of F, Cl, Bror —CF₃.

Embodiment 28. A compound according to any one of the embodiments 1 to27 wherein R³⁰, R³¹, R³² and R³³ are independently selected from thegroup consisting of

-   -   halogen, hydroxy, carboxy, —CF₃; or    -   —NR¹⁰R¹¹; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₁₋₆-alkoxy, C₃₋₆-alkenyloxy,        C₃₋₈-cycloalkyl, C₃₋₈-cycloalkoxy, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, C₃₋₈-cycloalkenyl-C₁₋₆-alkoxy, each        of which is optionally substituted with one or more substituents        independently selected from R¹²; or    -   Phenyl, phenoxy, benzyloxy, indanyloxy, benzo[1,3]dioxolyloxy,        phenylthio, or benzylthio; or    -   —C(O)—R²⁷, —S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, or —S(O)₂—NR¹³R¹⁴; or    -   two substituents selected from R³⁰, R³¹, R³² or R³³ attached to        the same or adjacent atoms together may form a radical        —O—(CH₂)1-3-O—.

Embodiment 29. A compound according to embodiment 28 wherein R³⁰, R³¹,R³² and R³³ are independently selected from the group consisting of

halogen, —CF₃, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₁₋₆-alkoxy, phenoxy, phenyl,benzyloxy, phenylthio, benzylthio, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkoxy, orC₃₋₆-cycloalkyl-C₁₋₆-alkoxy, each of which is optionally substitutedwith one or more substituents independently selected from R¹²; or—C(O)—R²⁷, —S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, or —S(O)₂—NR¹³R¹⁴.

Embodiment 30. A compound according to embodiment 28 wherein R³⁰, R³¹,R³² and R³³ are independently selected from the group consisting of F,Cl, Br, —CF₃, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl,ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, phenyl, methoxy, ethoxy, propoxy, butoxy, tert-butoxy,cyclohexyloxy, phenoxy, benzyloxy, indanyloxy, benzo[1,3]dioxolyloxy,cyclopropyl-methoxy, cyclopropyl-ethoxy, cyclopropyl-propoxy,cyclobutyl-methoxy, cyclobutyl-ethoxy, cyclobutyl-propoxy,cyclopentyl-methoxy, cyclopentyl-ethoxy, cyclopentyl-propoxy,cyclohexyl-methoxy, cyclohexyl-ethoxy, cyclohexyl-propoxy,cycloheptyl-methoxy, cycloheptyl-ethoxy, cycloheptyl-propoxy, phenylthioor benzylthio, each of which is optionally substituted with one or moresubstituents independently selected from R¹²; or —C(O)—R²⁷, —S(O)₂—R²⁷,—C(O)—NR¹³R¹⁴, or —S(O)₂—NR¹³R¹⁴.

Embodiment 31. A compound according to embodiment 30 wherein R³⁰, R³¹,R³² and R³³ are independently selected from the group consisting ofmethyl, ethyl, propyl, butyl, isopropyl, tert-butyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy,tert-butoxy, phenyl, phenoxy, benzyloxy, cyclopropyl-methoxy,cyclopropyl-ethoxy, cyclobutyl-methoxy, cyclobutyl-ethoxy,cyclopentyl-methoxy, cyclopentyl-ethoxy, cyclohexyl-methoxy,cyclohexyl-ethoxy, each of which is optionally substituted with one ormore substituents independently selected from R¹².

Embodiment 32. A compound according to embodiment 31 wherein R³⁰, R³¹,R³² and R³³ are independently selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, tertbutyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, propoxy, butoxy,tert-butoxy, benzyloxy, or cyclopropyl-methoxy, each of which isoptionally substituted with one or more substituents independentlyselected from R¹².

Embodiment 33. A compound according to embodiment 32 wherein R³⁰, R³¹,R³² and R³³ are independently selected from the group consisting ofmethyl or ethyl, each of which is optionally substituted with one ormore substituents independently selected from R¹².

Embodiment 34. A compound according to embodiment 32 wherein R³⁰, R³¹,R³² and R³³ are independently selected from the group consisting ofcyclopentyl or cyclohexyl optionally substituted with one or moresubstituents independently selected from R¹².

Embodiment 35. A compound according to any one of the embodiments 1 to34 wherein R¹⁰ and R¹¹ independently represent hydrogen, C₁₋₆-alkyl,—C(O)—C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —C(O)—C₃₋₈-cycloalkyl, or—S(O)₂—C₁₋₆-alkyl.

Embodiment 36. A compound according to embodiment 35 wherein R¹⁰ and R¹¹independently represent hydrogen, —C(O)—C₁₋₆-alkyl,—C(O)—C₃₋₈-cycloalkyl, or —S(O)₂—C₁₋₆-alkyl.

Embodiment 37. A compound according to embodiment 35 wherein R¹⁰ and R¹¹independently represent hydrogen, methyl, ethyl, propyl, butyl,—C(O)-methyl, —C(O)-ethyl, —C(O)-propyl, —C(O)-isopropyl, —C(O)-butyl,—C(O)-cyclopentyl, —S(O)₂-methyl, carboxy-ethyl, carboxy-propyl orcarboxy-butyl.

Embodiment 38. A compound according to any one of the embodiments 1 to37 wherein R²⁷ is C₁₋₆-alkyl, C₁₋₆-alkoxy, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl,aryl-C₂₋₆-alkenyl, heteroaryl, heteroaryl-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkylthio-C₁₋₆-alkyl,R¹⁰HN—C₁₋₆-alkyl, R¹⁰R¹¹N—C₁₋₆-alkyl, R¹⁰R¹¹N—S(O)₂—C₁₋₆-alkyl, orR¹⁰R¹¹N—C(O)—C₁₋₆-alkyl, each of which is optionally substituted withone or more substituents independently selected from R¹².

Embodiment 39. A compound according to embodiment 38 wherein R²⁷ isC₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,aryl-C₁₋₆-alkyl, aryl-C₂₋₆-alkenyl, aryl, heteroaryl,heteroaryl-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl,R¹⁰HN—C₁₋₆-alkyl, R¹⁰R¹¹N—C₁₋₆-alkyl, R¹⁰R¹¹N—S(O)₂—C₁₋₆-alkyl, orR¹⁰R¹¹N—C(O)—C₁₋₆-alkyl, each of which is optionally substituted withone or more substituents independently selected from R¹².

Embodiment 40. A compound according to embodiment 39 wherein R²⁷ isC₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,aryl, heteroaryl-C₁₋₆-alkyl, aryl-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, or heteroaryl, each of which is optionallysubstituted with one or more substituents independently selected fromR¹².

Embodiment 41. A compound according to embodiment 40 wherein R²⁷ ismethyl, ethyl, propyl, n-butyl, isobutyl, cyclopropyl, cyclopentyl,cyclopropylmethyl, phenyl, pyridyl, thiophene, imidazole, or thiazole,each of which is optionally substituted with one or more substituentsindependently selected from R¹².

Embodiment 42. A compound according to embodiment 41 wherein R²⁷ ismethyl, ethyl, propyl, n-butyl, isobutyl, cyclopropyl, cyclopentyl,cyclopropylmethyl, phenyl, pyridyl, thiophene, imidazole, orthiazole.

Embodiment 43. A compound according to embodiment 42 wherein R²⁷ ismethyl, ethyl, or propyl.

Embodiment 44. A compound according to any one of the embodiments 1 to43 wherein R¹² is halogen, —CF₃, —CN, C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, C₂₋₆-alkenyloxy, C₃₋₈-cycloalkyloxy,C₃₋₈-cycloalkenyloxy, aryloxy, aryl-C₁₋₆-alkoxy, aryl-C₁₋₆-alkenyloxy,C₃₋₈-cycloalkyl-C₁₋₆-alkoxy, C₃₋₈-cycloalkyl-C₁₋₆-alkenyloxy,C₃₋₈-heterocyclyl-C₁₋₆-alkoxy, or C₃₋₈-heterocyclyl-C₁₋₆-alkenyloxy,each of which is optionally substituted with one or more substituentsindependently selected from R³⁸; or NR¹⁰R¹¹, or —S(O)₂—C₁₋₆-alkyl.

Embodiment 45. A compound according to embodiment 44 wherein R¹² ishalogen, —CF₃, —CN, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,C₃₋₈-cycloalkyloxy, aryloxy, aryl-C₁₋₆-alkoxy,C₃₋₈-cycloalkyl-C₁₋₆-alkoxy, or C₃₋₈-heterocyclyl-C₁₋₆-alkoxy, each ofwhich is optionally substituted with one or more substituentsindependently selected from R³⁸; or NR¹⁰R¹¹, or —S(O)₂—C₁₋₆-alkyl.

Embodiment 46. A compound according to embodiment 45 wherein R¹² is F,Cl, Br, —CF₃, —CN, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl,methoxy, methylthio, ethoxy, propoxy, butoxy, phenoxy, benzyloxy,cyclopropyl-methoxy, cyclopropyl-ethoxy, cyclobutyl-methoxy,cyclobutyl-ethoxy, cyclopentyl-methoxy, cyclopentyl-ethoxy,cyclohexyl-methoxy, cyclohexyl-ethoxy, —NHC(O)CH₃, or —S(O)₂—CH₃.

Embodiment 47. A compound according to embodiment 46 wherein R¹² is F,Cl, Br, —CF₃, —CN, methyl, ethyl, isopropyl, tert-butyl, methoxy,methylthio, ethoxy, cyclopropyl-methoxy, —NHC(O)CH₃, or —S(O)₂—CH₃.

Embodiment 48. A compound according to embodiment 47 wherein R¹² is F,Cl, Br, methyl or ethyl.

Embodiment 49. A compound according to any one of the embodiments 1 to48 wherein R¹³ and R¹⁴ are independently selected from hydrogen andC₁₋₆-alkyl; or R¹³ and R¹⁴ together with the nitrogen to which they areattached form a 3 to 8 membered heterocyclic ring with the said nitrogenatom.

Embodiment 50. A compound according to any one of the embodiments 1 to49 wherein R¹⁵ is selected from F, Cl, Br, hydroxy, carboxy, —CF₃, orC₁₋₆-alkyl.

Embodiment 51. A compound according to any one of the embodiments 1 to50 wherein R³⁸ is F, Cl, Br, methyl or ethyl.

Embodiment 52. A compound according to any one of the embodiments 1 to51 wherein A is

Embodiment 53. A compound according to embodiment 52 wherein A is

Embodiment 54. A compound according to embodiment 53 wherein A is

Embodiment 55. A compound according to any one of the embodiments 1 to54 wherein A is substituted with at least one substituent R⁷, R⁸ or R⁹independently selected from

-   -   C₁₋₆-alkyl, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio, each of which        is substituted with one or more substituents independently        selected from R³⁴; or    -   —C₁₋₆-alkyl-NR¹⁹R²⁰, —S(O)₂—R²¹, —S(O)₂—NR¹⁹R²⁰ or        —S(O)₂—N(R¹⁹)(C₁₋₆alkyl)-C(O)—NR²²R²³, each of which is        substituted with one or more substituents independently selected        from R²⁵; or    -   —C(O)—O—C₁₋₆-alkyl, C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, or        carboxy-C₁₋₆-alkyl, each of which is optionally substituted with        one or more substituents independently selected from R¹⁶; or    -   C₃₋₈-cycloalkyl or C₃₋₈-cycloalkylthio, each of which is        optionally substituted on the cycloalkyl part with one or more        substituents independently selected from R¹⁸; or    -   —C₁₋₆-alkyl-NR³⁶R³⁷, or —S(O)₂—NR³⁶R³⁷, each optionally        substituted with one or more substituents independently selected        from R²⁵; or    -   —C₁₋₆-alkyl-C(O)NR³⁶R³⁷ or        —C₁₋₆-alkyl-NH—C(O)—C₁₋₆-alkyl-NR²²R²³, each optionally        substituted with one or more substituents independently selected        from R²⁶.

Embodiment 56. A compound according to embodiment 55 wherein A issubstituted with at least one substituent R⁷, R⁸ or R⁹ independentlyselected from

-   -   C₁₋₆-alkyl, C₁₋₆-alkylthio substituted with one or more        substituents independently selected from R³⁴; or    -   —S(O)₂—R²¹, —S(O)₂—NR¹⁹R²⁰, or        —S(O)₂—N(R¹⁹)(C₁₋₆-alkyl)-C(O)—NR²²R²³; or    -   —C(O)—O—C₁₋₆-alkyl, which is optionally substituted with one or        more substituents independently selected from R¹⁶.

Embodiment 57. A compound according to embodiment 56 wherein A issubstituted with at least one substituent R⁷, R⁸ or R⁹ independentlyselected from

-   -   methylthio, ethylthio, propylthio, isopropylthio, butylthio or        2-methylpropylthio, each of which is substituted with one or        more substituents independently selected from R³⁴; or    -   —S(O)₂—R²¹, —S(O)₂—NR¹⁹R²⁰, or —S(O)₂—N(R¹⁹)—CH₂—C(O)—NR²²R²³.

Embodiment 58. A compound according to embodiment 57 wherein A issubstituted with at least one substituent R⁷, R⁸ or R⁹ independentlyselected from

-   -   methylthio, isopropylthio, ethylthio, or 2-methylpropylthio each        of which is substituted with one or more substituents        independently selected from R³⁴.

Embodiment 59. A compound according to embodiment 57 wherein R⁷, R⁸ orR⁹ are independently selected from —S(O)₂—R²¹.

Embodiment 60. A compound according to any one of the embodiments 1 to59 wherein if more than one substituent R⁷, R⁸ and R⁹ is present on Athat additional R⁷, R⁸ and R⁹ may be selected from methyl, ethyl,propyl, butyl, Cl, F, or Br.

Embodiment 61. A compound according to any one of the embodiments 1 to60 wherein R¹⁶, R¹⁷, and R¹⁸ are independently halogen, carboxy, orcarboxy-C₁₋₆-alkyl.

Embodiment 62. A compound according to any one of the embodiments 1 to61 wherein R³⁴ is carboxy, carboxy-C₁₋₆-alkyl, or —C(O)—O—C₁₋₆-alkyl.

Embodiment 63. A compound according to embodiment 62 wherein R³⁴ iscarboxy.

Embodiment 64. A compound according to any one of the embodiments 1 to63 wherein R¹⁹ and R²⁰ independently represent hydrogen, C₁₋₆-alkyl orcarboxy-C₁₋₆-alkyl, or R¹⁹ and R²⁰ together with the nitrogen to whichthey are attached form a 3 to 8 membered heterocyclic ring with the saidnitrogen atom, the heterocyclic ring optionally containing one or twofurther heteroatoms selected from nitrogen, oxygen and sulphur, theheterocyclic ring is optionally substituted with one or moresubstituents independently selected from R²⁴.

Embodiment 65. A compound according to any one of the embodiments 1 to64 wherein R²¹ is selected from C₁₋₆-alkyl or carboxy-C₁₋₆-alkyl.

Embodiment 66. A compound according to any one of the embodiments 1 to65 wherein R²² and R²³ are independently selected from C₁₋₆-alkyl.

Embodiment 67. A compound according to any one of the embodiments 1 to66 wherein R³⁶ and R³⁷ are independently selected fromcarboxy-C₁₋₆-alkyl.

Embodiment 68. A compound according to any one of the embodiments 1 to67 wherein R²⁴ is carboxy or carboxy-C₁₋₆-alkyl.

Embodiment 69. A compound according to any one of the embodiments 1 to68 wherein R²⁵ and R²⁶ are independently selected from carboxy orcarboxy-C₁₋₆-alkyl.

Embodiment 70. A compound according to any one of the embodiments 1 to69 wherein R²⁸ is C₁₋₆-alkyl, carboxy-C₃₋₈-cycloalkyl orcarboxy-C₁₋₆-alkyl.

Embodiment 71. A compound according to any one of the embodiments 1 to70 wherein R²⁹ is F, Cl, Br or carboxy.

Embodiment 72. A compound according to any one of the embodiments 1 to71 wherein R³⁵ is F, Cl, Br or carboxy.

In another embodiment, the present invention provides a novel compoundwherein the compound is selected from the following:

-   [2-(3-Cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic    acid;-   [2-(3-Butyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid;-   {2-[3-Cyclohexyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclohexyl-3-(2,2-dimethyl-propyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(2-Cyclohex-1-enyl-ethyl)-3-cyclohexyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   [2-(3-Bicyclo[2.2.1]hept-2-ylmethyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-acetic    acid;-   [2-(3-Bicyclo[2.2.1]hept-5-en-2-ylmethyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-acetic    acid;-   {2-[3-Cyclohexyl-3-(2-cyclohexyl-ethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   3-[2-(3-Cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-propionic    acid;-   3-[2-(3-Butyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-propionic    acid;-   3-{2-[3-Cyclohexyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-{2-[3-(trans-4-Methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-{2-[3-Butyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-{2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-{2-[3-(2-Cyclohex-1-enyl-ethyl)-3-cyclohexyl-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   {2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(trans-4-Methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(2-Cyclohex-1-enyl-ethyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Methyl-but-2-enyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   3-{2-[3-(3-Methyl-but-2-enyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   {2-[3-(4-trans-Ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(4-trans-Ethyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(2-Cyclohexyl-ethyl)-3-(4-trans-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   3-{2-[3-(4-trans-Ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-{2-[3-(4-trans-Ethyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-{2-[3-(2-Cyclohexyl-ethyl)-3-(4-trans-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   2-{2-[3-(4-trans-Ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic    acid;-   2-{2-[3-(4-trans-Ethyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic    acid;-   {2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylamino}-acetic    acid;-   3-{2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylamino}-propionic    acid;-   (Methyl-{2-[3-(3-methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-amino)-acetic    acid;-   (S)-1-{2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-pyrrolidine-2-carboxylic    acid;-   {2-[3-(4-trans-tert-Butyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(4-trans-Isopropyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   3-{2-[3-(4-trans-tert-Butyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-{2-[3-(4-trans-Isopropyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   {2-[3-(4-Methyl-cyclohexyl)-3-(3-phenyl-propyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Methyl-butyl)-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(trans-4-tert-Butoxy-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(trans-4-Cyclopropylmethoxy-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[trans-4-(2-Methoxy-ethoxy)-cyclohexyl]-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(trans-4-Benzyloxy-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(trans-4-Methoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(trans-4-Ethoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(trans-4-Cyclopropylmethoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Butyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3,3-Bis-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Butyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   3-{2-[3,3-Bis-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   2-[3-(4-trans-Ethyl-cyclohexyl)-3-(2-phenoxy-ethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(4-trans-Ethyl-cyclohexyl)-3-(4-phenoxy-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   3-{2-[3-Butyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   2-Methyl-2-{2-[3-(3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   2-{2-[3-Cyclohexyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic    acid;-   5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazole-2-carboxylic    acid ethyl ester;-   {5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-ylsulfanyl}-acetic    acid ethyl ester;-   2-Methyl-2-{5-[3-(3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-ylsulfanyl}-propionic    acid;-   {5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-ylsulfanyl}-acetic    acid;-   3-{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-ylsulfanyl}-propionic    acid ethyl ester;-   3-{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-yl}-propionic    acid methyl ester;-   {2-[3-(1,3-Dimethyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   2-{2-[3-(1,3-Dimethyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic    acid;-   3-{2-[3-(1,3-Dimethyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-ylsulfanyl}-propionic    acid;-   3-{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-yl}-propionic    acid;-   {2-[3-(2-Benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(2-Isopropoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(2-tert-Butoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(2-Cyclohexyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-acetic    acid;-   {2-[3-(2-Ethoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(2-Iso-butoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;

(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2,2,2-trifluoro-ethoxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid;

-   {2-[3-(3-Methoxy-3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   3-{2-[3-(2-Benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-{2-[3-(2-Iso-propoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-{2-[3-(2-tert-Butoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-{2-[3-(2-Cyclohexyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-propionic    acid;-   3-{2-[3-(2-Iso-butoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2,2,2-trifluoro-ethoxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-propionic    acid;-   3-{2-[3-(3-Methoxy-3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   {2-[3-(4-trans-methyl-cyclohexyl)-3-(2-phenoxy-ethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Ethoxy-propyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Methoxy-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Benzyloxy-propyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   3-{2-[3-(4-trans-methyl-cyclohexyl)-3-(2-phenoxy-ethyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-{2-[3-(3-Ethoxy-propyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   {2-[3-(2-Benzyloxy-1-methyl-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   3-{2-[3-(2-Benzyloxy-1-methyl-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   {2-[3-[2-(2-Chloro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(3-Chloro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(4-Chloro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(2-Methoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(3-Methoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(4-Methoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;

(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(1-phenyl-ethoxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid;

(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2-trifluoromethylsulfanyl-benzyloxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid;

-   {2-[3-[2-(2-Cyano-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(4-Fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(4-Fluoro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(2-Fluoro-6-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(4-trans-methyl-cyclohexyl)-3-(2-phenyl-propyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(2-Chloro-4-fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(4-trans-methyl-cyclohexyl)-3-(2-p-tolyl-ethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(4-trans-methyl-cyclohexyl)-3-(2-pentafluorophenylmethoxy-ethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(4-trifluoromethyl-phenyl)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-acetic    acid;-   {2-[3-[2-(4-Ethoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(4-Isopropoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(4-propoxy-phenyl)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-acetic    acid;-   {2-[3-[2-(2-Fluoro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(3-Fluoro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(4-Isopropyl-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(3-Fluoro-4-methoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(3-Fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(3-trifluoromethyl-benzyloxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-acetic    acid;-   {2-[3-[2-(4-Methanesulfonyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(4-trifluoromethyl-benzyloxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-acetic    acid;-   (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2-trifluoromethyl-benzyloxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-acetic    acid;-   {2-[3-[2-(2-Methoxy-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(4-tert-Butyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(4-trifluoromethoxy-benzyloxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-acetic    acid;-   {2-[3-[2-(2,4-Difluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(4-Isopropyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(4-Fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(3-trifluoromethoxy-benzyloxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-acetic    acid;-   {2-[3-[2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(2,3-Difluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(2,6-Difluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[3-(4-Methoxy-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[3-(4-Fluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[3-(Indan-5-yloxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[3-(3,4-Difluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[3-(2,4-Difluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[3-(4-tert-Butyl-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[3-(4-Isopropyl-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[3-(3-Acetylamino-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[3-(2-Fluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[3-(3-Isopropyl-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[3-(Benzo[1,3]dioxol-5-yloxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   (2-{3-(4-trans-methyl-cyclohexyl)-3-[3-(4-trifluoromethoxy-phenoxy)-propyl]-ureido}-thiazol-5-ylsulfanyl)-acetic    acid;-   (2-{3-(4-trans-methyl-cyclohexyl)-3-[3-(3-trifluoromethoxy-phenoxy)-propyl]-ureido}-thiazol-5-ylsulfanyl)-acetic    acid;-   {2-[3-[3-(3-Fluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   3-{2-[3-[3-(2-Chloro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-{2-[3-[3-(4-Chloro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   {2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   2-{2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic    acid;-   2-({2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonyl}-methyl-amino)-N,N-diethyl-acetamide;-   (S)-1-{2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonyl}-pyrrolidine-2-carboxylic    acid;-   {2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonylamino}-acetic    acid;-   3-{2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonylamino}-propionic    acid;-   {2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   2-{2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic    acid;-   (S)-1-{2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazole-5-sulfonyl}-pyrrolidine-2-carboxylic    acid;-   {2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazole-5-sulfonylamino}-acetic    acid;-   3-{2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazole-5-sulfonylamino}-propionic    acid;-   3-{2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-{2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   {2-[3-(3-Acetylamino-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   3-{2-[3-(3-Acetylamino-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   {2-[3-Cyclopentylmethyl-3-(3-dimethylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   3-{2-[3-Cyclopentylmethyl-3-(3-dimethylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   {2-[3-(3-Carbamoyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   3-{2-[3-(3-Carbamoyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   {2-[3-Cyclopentylmethyl-3-(3-methylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   3-{2-[3-Cyclopentylmethyl-3-(3-methylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   {2-[3-Cyclopentylmethyl-3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(4-sulfamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(4-fluoro-3-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(4-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(3-sulfamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   [2-(3-Benzo[1,3]dioxol-5-yl-3-cyclopentylmethyl-ureido)-thiazol-5-ylsulfanyl]-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(3-trifluoromethoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(6-methoxy-pyridin-3-yl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(6-Acetylamino-pyridin-3-yl)-3-cyclopentyl    methyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid;-   {2-[3-(3-Acetylamino-phenyl)-3-pentyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Acetylamino-phenyl)-3-cyclohexylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Acetylamino-phenyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Acetylamino-phenyl)-3-hexyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Acetylamino-phenyl)-3-cyclopropylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Acetylamino-phenyl)-3-(3,3-dimethyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclohexylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   [2-(3-Benzo[1,3]dioxol-5-yl-3-cyclohexyl    methyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid;-   {2-[3-Cyclohexylmethyl-3-(6-methoxy-pyridin-3-yl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(3-ethylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclobutylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(3-isopropylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   (2-{3-[3-(Azetidine-1-carbonyl)-phenyl]-3-cyclopentyl    methyl-ureido}-thiazol-5-ylsulfanyl)-acetic acid;-   {2-[3-(3,4-Difluoro-phenyl)-3-(4-methyl-cyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3,4-Difluoro-phenyl)-3-(4-trifluoromethyl-cyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(4-tert-Butyl-cyclohexylmethyl)-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Chloro-4-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(2,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(2,3-dichloro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(3-fluoro-4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Acetylamino-phenyl)-3-benzyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Acetylamino-phenyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(2-Cyclopentylethyl)-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3,4-Difluoro-phenyl)-3-(trans-4-methyl-cyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Acetylamino-4-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(3-propionylamino-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(3-isobutyrylamino-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   (2-{3-[3-(Cyclopentanecarbonyl-amino)-phenyl]-3-cyclopentylmethyl-ureido}-thiazol-5-ylsulfanyl)-acetic    acid;-   {2-[3-(trans-4-Methyl-cyclohexylmethyl)-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclohexylmethyl-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(2,3-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Chloro-4-methoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid,-   {2-[3-Cyclopentylmethyl-3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(3-methanesulfonylamino-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(2,4,6-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Chloro-2-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid,-   {2-[3-Cyclopentylmethyl-3-(4-fluoro-3-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(2,3-difluoro-4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(4-isopropoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(3-fluoro-2-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Chloro-2-methoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Chloro-2-methyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(2-fluoro-3-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-[2-(3,4-Difluoro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   (2-{3-(4-trans-Methyl-cyclohexyl)-3-[2-(3,4,5-trifluoro-phenyl)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-acetic    acid;-   (2-{3-(4-trans-Methyl-cyclohexyl)-3-[2-(2,4,5-trifluoro-phenyl)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-acetic    acid;-   (2-{3-(4-trans-Methyl-cyclohexyl)-3-[2-(2,3,4-trifluoro-phenyl)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-acetic    acid;-   2-{2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic    acid;-   2-{2-[3-[2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic    acid;-   {2-[3-(2-Chloro-3-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Bromo-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(4-Bromo-2-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(2-Bromo-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-Cyclopentylmethyl-3-(3-methoxy-5-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(3-Acetyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   {2-[3-(2-Benzyloxy-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-acetic    acid;-   {2-[3-[2-(2-Methyl-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-acetic    acid;-   {2-[3-[2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-acetic    acid;-   {2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-acetic    acid;-   (2-{3-(4-Methyl-cyclohexyl)-3-[2-(2-trifluoromethyl-benzyloxy)-ethyl]-ureido}-thiazole-5-sulfonyl)-acetic    acid;-   {2-[3-[2-(4-Fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-acetic    acid;-   {2-[3-[2-(2-Chloro-4-fluoro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-acetic    acid;-   {2-[3-[2-(2,4-Difluoro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-acetic    acid;-   2-{2-[3-(2-Benzyloxy-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2-methyl-propionic    acid;-   2-Methyl-2-{2-[3-[2-(2-methyl-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-propionic    acid;-   2-{2-[3-[2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2-methyl-propionic    acid;-   2-{2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2-methyl-propionic    acid;-   2-Methyl-2-(2-{3-(4-methyl-cyclohexyl)-3-[2-(2-trifluoromethyl-benzyloxy)-ethyl]-ureido}-thiazole-5-sulfonyl)-propionic    acid;-   2-{2-[3-[2-(4-Fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2-methyl-propionic    acid;-   2-{2-[3-[2-(2,4-Difluoro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2-methyl-propionic    acid;-   {2-[3-(4-Methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazole-5-sulfonyl}-acetic    acid;-   2-Methyl-2-{2-[3-(4-methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazole-5-sulfonyl}-propionic    acid;-   {2-[3-(4-Methyl-cyclohexyl)-3-phenethyl-ureido]-thiazole-5-sulfonyl}-acetic    acid;-   {2-[3-[2-(4-Methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-acetic    acid;-   {2-[3-[2-(3-Fluoro-4-methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-acetic    acid;-   {2-[3-[2-(4-Ethoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-acetic    acid;-   2-Methyl-2-{2-[3-(4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazole-5-sulfonyl}-propionic    acid;-   2-{2-[3-[2-(4-Methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2-methyl-propionic    acid;-   2-{2-[3-[2-(3-Fluoro-4-methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2-methyl-propionic    acid;-   2-{2-[3-[2-(3-Fluoro-4-methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2-methyl-propionic    acid;-   3-{2-[3-(2-Benzyloxy-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic    acid;-   3-{2-[3-[2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic    acid;-   2,2-Dimethyl-3-{2-[3-[2-(2-methyl-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-{2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic    acid;-   2,2-Dimethyl-3-(2-{3-(4-methyl-cyclohexyl)-3-[2-(2-trifluoromethyl-benzyloxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-propionic    acid;-   2,2-Dimethyl-3-{2-[3-(4-methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-{2-[3-[3-(2-Chloro-phenoxy)-propyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic    acid;-   3-{2-[3-[3-(3-Chloro-phenoxy)-propyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic    acid;-   3-{2-[3-[3-(4-Chloro-phenoxy)-propyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic    acid;-   2,2-Dimethyl-3-{2-[3-(4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   3-{2-[3-[2-(4-Methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic    acid;-   3-{2-[3-[2-(4-Ethoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic    acid;-   3-{2-[3-[2-(3-Fluoro-4-methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic    acid;-   {2-[3-(2-Benzylsulfanyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   2-{2-[3-(2-Benzylsulfanyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic    acid;-   {2-[3-(2-Benzylsulfanyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-acetic    acid;-   2-{2-[3-(2-Benzylsulfanyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2-methyl-propionic    acid;-   3-{2-[3-(2-Benzylsulfanyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic    acid;-   3-{2-[3-(2-Benzylsulfanyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2,2-dimethyl-propionic    acid;-   2,2-Dimethyl-3-{2-[3-(4-methyl-cyclohexyl)-3-(3-phenylsulfanyl-propyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   2,2-Dimethyl-3-{2-[3-(4-methyl-cyclohexyl)-3-(3-phenylsulfanyl-propyl)-ureido]-thiazole-5-sulfonyl}-propionic    acid;-   {2-[3-(4-Methyl-cyclohexyl)-3-(3-phenylsulfanyl-propyl)-ureido]-thiazol-5-ylsulfanyl}-acetic    acid;-   2-Methyl-2-{2-[3-(4-methyl-cyclohexyl)-3-(3-phenylsulfanyl-propyl)-ureido]-thiazol-5-ylsulfanyl}-propionic    acid;-   {2-[3-(4-Methyl-cyclohexyl)-3-(3-phenylsulfanyl-propyl)-ureido]-thiazole-5-sulfonyl}-acetic    acid;-   2-Methyl-2-{2-[3-(4-methyl-cyclohexyl)-3-(3-phenylsulfanyl-propyl)-ureido]-thiazole-5-sulfonyl}-propionic    acid;    or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a novelpharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a compound of the present invention, or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the present invention provides a novel method oftreating type 2 diabetes, comprising: administering to a subject in needthereof a therapeutically effective amount of a compound of the presentinvention.

In one aspect the invention provides a method of preventing hypoglycemiacomprising administration of a compound according to the presentinvention.

In another aspect the invention provides the use of a compound accordingto the present invention for the preparation of a medicament for theprevention of hypoglycemia.

In another aspect the invention provides a compound as described herein,which is an agent useful for the treatment of an indication selectedfrom the group consisting of hyperglycemia, IGT, insulin resistancesyndrome, syndrome X, type 2 diabetes, type 1 diabetes, dyslipidemia,hypertension, and obesity.

In another aspect the invention provides a compound as described hereinfor use as a medicament.

In another aspect the invention provides a compound as described hereinfor treatment of hyperglycemia, for treatment of IGT, for treatment ofSyndrome X, for treatment of type 2 diabetes, for treatment of type 1diabetes, for treatment of dyslipidemia, for treatment ofhyperlipidemia, for treatment of hypertension, for treatment of obesity,for lowering of food intake, for appetite regulation, for regulatingfeeding behaviour, or for enhancing the secretion of enteroincretins,such as GLP-1.

In another aspect the invention provides a pharmaceutical compositioncomprising, as an active ingredient, at least one compound as describedherein together with one or more pharmaceutically acceptable carriers orexcipients.

In one embodiment such a pharmaceutical composition may be in unitdosage form, comprising from about 0.05 mg to about 1000 mg, preferablyfrom about 0.1 mg to about 500 mg and especially preferred from about0.5 mg to about 200 mg of the compound according to the presentinvention.

In another aspect the invention provides the use of a compound accordingto the invention for increasing the activity of glucokinase.

In another aspect the invention provides the use of a compound accordingto the invention for the preparation of a medicament for the treatmentof metabolic disorders, for blood glucose lowering, for the treatment ofhyperglycemia, for the treatment of IGT, for the treatment of SyndromeX, for the treatment of impaired fasting glucose (IFG), for thetreatment of type 2 diabetes, for the treatment of type 1 diabetes, fordelaying the progression of impaired glucose tolerance (IGT) to type 2diabetes, for delaying the progression of non-insulin requiring type 2diabetes to insulin requiring type 2 diabetes, for the treatment ofdyslipidemia, for the treatment of hyperlipidemia, for the treatment ofhypertension, for lowering of food intake, for appetite regulation, forthe treatment of obesity, for regulating feeding behaviour, or forenhancing the secretion of enteroincretins. In another aspect theinvention provides the use of a compound according to the invention forthe preparation of a medicament for the adjuvant treatment of type 1diabetes for preventing the onset of diabetic complications.

In another aspect the invention provides the use of a compound accordingto the invention for the preparation of a medicament for increasing thenumber and/or the size of beta cells in a mammalian subject, fortreatment of beta cell degeneration, in particular apoptosis of betacells, or for treatment of functional dyspepsia, in particular irritablebowel syndrome. In one embodiment the invention provides any of theabove uses in a regimen which comprises treatment with a furtherantidiabetic agent.

In a further aspect the invention provides the use of a compoundaccording to the invention or a pharmaceutical composition as describedabove for the treatment of metabolic disorders, for blood glucoselowering, for the treatment of hyperglycemia, for treatment of IGT, fortreatment of Syndrome X, for the treatment of impaired fasting glucose(IFG), for treatment of type 2 diabetes, for treatment of type 1diabetes, for delaying the progression of impaired glucose tolerance(IGT) to type 2 diabetes, for delaying the progression of non-insulinrequiring type 2 diabetes to insulin requiring type 2 diabetes, fortreatment of dyslipidemia, for treatment of hyperlipidemia, fortreatment of hypertension, for the treatment or prophylaxis of obesity,for lowering of food intake, for appetite regulation, for regulatingfeeding behaviour, or for enhancing the secretion of enteroincretins.

In a further aspect the invention provides the use of a compoundaccording to the invention or a pharmaceutical composition as describedabove for the adjuvant treatment of type 1 diabetes for preventing theonset of diabetic complications.

In a further aspect the invention provides the use of a compoundaccording to the invention or a pharmaceutical composition as describedabove for increasing the number and/or the size of beta cells in amammalian subject, for treatment of beta cell degeneration, inparticular apoptosis of beta cells, or for treatment of functionaldyspepsia, in particular irritable bowel syndrome.

In another embodiment the invention provides a for the treatment of aglucokinase-deficiency mediated condition/disease which is caused by aglucokinase mutation.

In another embodiment the invention provides a method wherein theglucokinase-deficiency mediated condition/disease is Maturity-OnsetDiabetes of the Young, Neonatal Diabetes Mellitus, or PersistentNeonatal Diabetes Mellitus.

In another embodiment the invention provides a method for preventing orameliorating the development of diabetes in subjects exhibiting symptomsof Impaired Glucose Tolerance, Gestational Diabetes Mellitus, PolycysticOvarian Syndrome, Cushings syndrome or Metabolic Syndrome comprisingadministering to a subject in need of such treatment a compoundaccording to the invention or pharmaceutical composition thereof,wherein blood glucose normalization occurs with reduced risk ofhypoglycemia.

In another embodiment the invention provides a method for preventing orameliorating microvascular diseases comprising administering to asubject in need of such treatment a compound according to the inventionor pharmaceutical composition thereof.

In another embodiment the invention provides a method for preventingmacrovascular diseases in subjects exhibiting symptoms of ImpairedGlucose Tolerance, Gestational Diabetes Mellitus, or Metabolic Syndrome,comprising administering to a subject in need of such treatment acompound according to the invention or pharmaceutical compositionthereof, alone or in combination with lipid-lowering drugs, whereinblood glucose normalization occurs with reduced risk of hypoglycemia.

In another embodiment the invention provides a method for thepreservation of beta-cell mass and function comprising administering toa subject in need of such treatment a compound according to theinvention or pharmaceutical composition thereof, wherein blood glucosenormalization occurs with reduced risk of hypoglycemia.

In another embodiment the invention provides a method for preventingamyloid beta peptide induced cell death comprising administering to asubject in need of such treatment a compound according to the inventionor pharmaceutical composition thereof, wherein blood glucosenormalization occurs with reduced risk of hypoglycemia.

In another embodiment the invention provides a method wherein thesubject is a veterinary subject.

In another embodiment the invention provides a method wherein a compoundaccording to the invention is administered as a food additive.

In another embodiment the invention provides a method for the treatmentof hepatic conditions benefiting from blood glucose normalizationcomprising administering to a subject in need of such treatment acompound according to the invention or pharmaceutical compositionthereof, wherein blood glucose normalization occurs with reduced risk ofhypoglycemia.

In another embodiment the invention provides a method for the treatmentof hepatic conditions benefiting from improved liver function comprisingadministering to a subject in need of such treatment a compoundaccording to the invention or pharmaceutical composition thereof.

In another embodiment the invention provides a method for the treatmentof hyperglycemic conditions that result from critical illness, or as aconsequence of therapeutic intervention comprising administering to asubject in need of such treatment a compound according to the inventionor pharmaceutical composition thereof, wherein blood glucosenormalization occurs with reduced risk of hypoglycemia.

In another embodiment the invention provides a method for the treatmentof hepatic conditions that result from critical illness like cancer, orare a consequence of therapy, for example cancer therapy orHIV-treatment, comprising administering to a subject in need of suchtreatment a compound according to the invention or pharmaceuticalcomposition thereof.

In another embodiment the invention provides a method of treatmentadjuvant to insulin in insulin-requiring diabetes type 2, or asreplacement for insulin comprising administering to a subject in need ofsuch treatment a compound according to the invention or pharmaceuticalcomposition thereof, wherein blood glucose normalization occurs withreduced risk of hypoglycemia.

In another embodiment the invention provides a method for the treatmentof lipodistrophy comprising administering to a subject in need of suchtreatment a compound according to the invention or pharmaceuticalcomposition thereof, wherein blood glucose normalization occurs withreduced risk of hypoglycemia.

In another embodiment the invention provides a method for the treatmentof hyperglycemia resulting from severe physical stress without signs ofliver failure comprising administering to a subject in need of suchtreatment a compound according to the invention or pharmaceuticalcomposition thereof, wherein blood glucose normalization occurs withreduced risk of hypoglycemia.

In another embodiment the invention provides a method wherein the severephysical stress is multiple trauma, or diabetic ketoacidosis.

In another embodiment the invention provides a method for preventingapoptotic liver damage comprising administering to a subject in need ofsuch treatment a compound according to the invention or pharmaceuticalcomposition thereof.

In another embodiment the invention provides a method for preventinghypoglycemia comprising administering to a subject in need of suchtreatment a compound according to the invention or pharmaceuticalcomposition thereof, wherein blood glucose normalization occurs withreduced risk of hypoglycemia.

In another embodiment the invention provides a method for increasingbeta-cell mass and function comprising administering to a subject inneed of such treatment a compound according to the invention orpharmaceutical composition thereof, wherein blood glucose normalizationoccurs with reduced risk of hypoglycemia.

In another embodiment the invention provides a method of preventing type1 diabetes comprising administering to a subject in need of suchtreatment a compound according to the invention or pharmaceuticalcomposition thereof, wherein blood glucose normalization occurs withreduced risk of hypoglycemia.

In another embodiment the invention provides a method of preservingand/or increasing beta-cell mass and function in patients havingundergone pancreatic islet transplantation comprising administering to asubject in need of such treatment a compound according to the inventionor pharmaceutical composition thereof.

In another embodiment the invention provides a method of improvingglucose control during and after surgery comprising administering to asubject in need of such treatment a compound according to the inventionor pharmaceutical composition thereof.

In another embodiment the invention provides a method of improving liverfunction and/or survival in patients undergoing liver transplantationcomprising administering to a subject in need of such treatment acompound according to the invention or pharmaceutical compositionthereof. In another embodiment hereof the invention provides a methodwherein the administration occurs before, during or aftertransplantation, or any combination thereof.

In another embodiment the invention provides a method of obtaining bloodglucose normalization comprising administering to a subject in need ofsuch treatment a compound according to the invention or pharmaceuticalcomposition thereof, wherein blood glucose normalization occurs withreduced risk of hypoglycemia.

In another embodiment the invention provides a method of preventing orameliorating diabetic late complications comprising administering to asubject in need of such treatment a compound according to the inventionor pharmaceutical composition thereof.

In another embodiment the invention provides a method of treating type 1or 2 diabetes comprising administering to a subject in need of suchtreatment a compound according to the invention or pharmaceuticalcomposition thereof, wherein the treatment does not result in a weightgain.

In another embodiment the invention provides a method of preventingdiabetic ketoacidosis comprising administering to a subject in need ofsuch treatment a compound according to the invention or pharmaceuticalcomposition thereof.

Combination Treatment

In a further aspect of the present invention the present compounds areadministered in combination with one or more further active substancesin any suitable ratios. Such further active agents may be selected fromantidiabetic agents, antihyperlipidemic agents, antiobesity agents,antihypertensive agents and agents for the treatment of complicationsresulting from or associated with diabetes.

Suitable antidiabetic agents include insulin, GLP-1 (glucagon likepeptide-1) derivatives such as those disclosed in WO 98/08871 (NovoNordisk A/S), which is incorporated herein by reference, as well asorally active hypoglycemic agents.

Suitable orally active hypoglycemic agents preferably includeimidazolines, sulfonylureas, biguanides, meglitinides,oxadiazolidinediones, thiazolidinediones, insulin sensitizers,α-glucosidase inhibitors, agents acting on the ATP-dependent potassiumchannel of the pancreatic β-cells eg potassium channel openers such asthose disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (NovoNordisk A/S) which are incorporated herein by reference, potassiumchannel openers, such as ormitiglinide, potassium channel blockers suchas nateglinide or BTS-67582, glucagon antagonists such as thosedisclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and AgouronPharmaceuticals, Inc.), all of which are incorporated herein byreference, GLP-1 agonists such as those disclosed in WO 00/42026 (NovoNordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporatedherein by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase(protein tyrosine phosphatase) inhibitors, inhibitors of hepatic enzymesinvolved in stimulation of gluconeogenesis and/or glycogenolysis,glucose uptake modulators, GSK-3 (glycogen synthase kinase-3)inhibitors, compounds modifying the lipid metabolism such asantihyperlipidemic agents and antilipidemic agents, compounds loweringfood intake, and PPAR (peroxisome proliferator-activated receptor) andRXR (retinoid X receptor) agonists such as ALRT-268, LG-1268 or LG-1069.

In one embodiment of the present invention, the present compounds areadministered in combination with a sulphonylurea eg tolbutamide,chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride,glicazide or glyburide.

In one embodiment of the present invention, the present compounds areadministered in combination with a biguanide eg metformin.

In one embodiment of the present invention, the present compounds areadministered in combination with a meglitinide eg repaglinide orsenaglinide/nateglinide.

In one embodiment of the present invention, the present compounds areadministered in combination with a thiazolidinedione insulin sensitizereg troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone,darglitazone, englitazone, CS-011/Cl-1037 or T 174 or the compoundsdisclosed in WO 97/41097 (DRF-2344), WO 97/41119, WO 97/41120, WO00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which areincorporated herein by reference.

In one embodiment of the present invention the present compounds may beadministered in combination with an insulin sensitizer eg such as GI262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544,CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or thecompounds disclosed in WO 99/19313 (NN622/DRF-2725), WO 00/50414, WO00/63191, WO 00/63192, WO 00/63193 (Dr. Reddy's Research Foundation) andWO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO00/63189 (Novo Nordisk A/S), which are incorporated herein by reference.

In one embodiment of the present invention the present compounds areadministered in combination with an α-glucosidase inhibitor egvoglibose, emiglitate, miglitol or acarbose. In one embodiment of thepresent invention the present compounds are administered in combinationwith a glycogen phosphorylase inhibitor eg the compounds described in WO97/09040 (Novo Nordisk A/S).

In one embodiment of the present invention the present compounds areadministered in combination with an agent acting on the ATP-dependentpotassium channel of the pancreatic β-cells eg tolbutamide,glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide. In oneembodiment of the present invention the present compounds areadministered in combination with nateglinide.

In one embodiment of the present invention the present compounds areadministered in combination with an antihyperlipidemic agent or aantilipidemic agent eg cholestyramine, colestipol, clofibrate,gemfibrozil, lovastatin, pravastatin, simvastatin, probucol ordextrothyroxine.

Furthermore, the compounds according to the invention may beadministered in combination with one or more antiobesity agents orappetite regulating agents.

Such agents may be selected from the group consisting of CART (cocaineamphetamine regulated transcript) agonists, NPY (neuropeptide Y)antagonists, MC3 (melanocortin 3) agonists, MC4 (melanocortin 4)agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF(corticotropin releasing factor) agonists, CRF BP (corticotropinreleasing factor binding protein) antagonists, urocortin agonists, β3adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884,LY377267 or AZ-40140, MSH (melanocyte-stimulating hormone) agonists, MCH(melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin)agonists, serotonin reuptake inhibitors (fluoxetine, seroxat orcitalopram), serotonin and norepinephrine reuptake inhibitors, 5HT(serotonin) agonists, bombesin agonists, galanin antagonists, growthhormone, growth factors such as prolactin or placental lactogen, growthhormone releasing compounds, TRH (thyreotropin releasing hormone)agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptinagonists, DA (dopamine) agonists (bromocriptin, doprexin),lipase/amylase inhibitors, PPAR modulators, RXR modulators, TR βagonists, adrenergic CNS stimulating agents, AGRP (agouti relatedprotein) inhibitors, H3 histamine antagonists such as those disclosed inWO 00/42023, WO 00/63208 and WO 00/64884, which are incorporated hereinby reference, exendin-4, GLP-1 agonists, ciliary neurotrophic factor,and oxyntomodulin. Further antiobesity agents are bupropion(antidepressant), topiramate (anticonvulsant), ecopipam (dopamine D1/D5antagonist) and naltrexone (opioid antagonist).

In one embodiment of the present invention the antiobesity agent isleptin.

In one embodiment of the present invention the antiobesity agent is aserotonin and norepinephrine reuptake inhibitor eg sibutramine.

In one embodiment of the present invention the antiobesity agent is alipase inhibitor eg orlistat.

In one embodiment of the present invention the antiobesity agent is anadrenergic CNS stimulating agent eg dexamphetamine, amphetamine,phentermine, mazindol phendimetrazine, diethylpropion, fenfluramine ordexfenfluramine.

Furthermore, the present compounds may be administered in combinationwith one or more antihypertensive agents. Examples of antihypertensiveagents are β-blockers such as alprenolol, atenolol, timolol, pindolol,propranolol and metoprolol, ACE (angiotensin converting enzyme)inhibitors such as benazepril, captopril, enalapril, fosinopril,lisinopril, quinapril and ramipril, calcium channel blockers such asnifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazemand verapamil, and a-blockers such as doxazosin, urapidil, prazosin andterazosin. Further reference can be made to Remington: The Science andPractice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co.,Easton, Pa., 1995.

In one embodiment of the present invention, the present compounds areadministered in combination with insulin, insulin derivatives or insulinanalogues.

In one embodiment of the invention the insulin is an insulin derivativeis selected from the group consisting of B29-N^(ε)-myristoyl-des(B30)human insulin, B29-N^(ε)-palmitoyl-des(B30) human insulin,B29-N^(ε)-myristoyl human insulin, B29-N^(ε)-palmitoyl human insulin,B28-N^(ε)-myristoyl Lys^(B28) Pro^(B29) human insulin,B28-N^(ε)-palmitoyl Lys^(B28) Pro^(B29) human insulin,B30-N^(ε)-myristoyl-Thr^(B29)Lys^(B30) human insulin,B30-N^(ε)-palmitoyl-Thr^(B29)Lys^(B30) human insulin,B29-N^(ε)-(N-palmitoyl-γ-glutamyl)-des(B30) human insulin,B29-N^(ε)-(N-lithocholyl-γ-glutamyl)-des(B30) human insulin,B29-N^(ε)-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N^(ε)-(ω-carboxyheptadecanoyl) human insulin.

In another embodiment of the invention the insulin derivative isB29-N^(ε)-myristoyl-des(B30) human insulin.

In a further embodiment of the invention the insulin is anacid-stabilised insulin. The acid-stabilised insulin may be selectedfrom analogues of human insulin having one of the following amino acidresidue substitutions:

A21G

A21G, B28K, B29P

A21G, B28D

A21G, B28E

A21G, B3K, B29E

A21G, desB27

A21G, B9E

A21G, B9D

A21G, B10E insulin.

In a further embodiment of the invention the insulin is an insulinanalogue. The insulin analogue may be selected from the group consistingof

An analogue wherein position B28 is Asp, Lys, Leu, Val, or Ala andposition B29 is Lys or Pro; and

des(B28-B30), des(B27) or des(B30) human insulin.

In another embodiment the analogue is an analogue of human insulinwherein position B28 is Asp or Lys, and position B29 is Lys or Pro.

In another embodiment the analogue is des(B30) human insulin.

In another embodiment the insulin analogue is an analogue of humaninsulin wherein position B28 is Asp.

In another embodiment the analogue is an analogue wherein position B3 isLys and position B29 is Glu or Asp.

In another embodiment the GLP-1 derivative to be employed in combinationwith a compound of the present invention refers to GLP-1 (1-37),exendin-4(1-39), insulinotropic fragments thereof, insulinotropicanalogues thereof and insulinotropic derivatives thereof. Insulinotropicfragments of GLP-1 (1-37) are insulinotropic peptides for which theentire sequence can be found in the sequence of GLP-1 (1-37) and whereat least one terminal amino acid has been deleted. Examples ofinsulinotropic fragments of GLP-1 (1-37) are GLP-1 (7-37) wherein theamino acid residues in positions 1-6 of GLP-1 (1-37) have been deleted,and GLP-1 (7-36) where the amino acid residues in position 1-6 and 37 ofGLP-1 (1-37) have been deleted. Examples of insulinotropic fragments ofexendin-4(1-39) are exendin-4(1-38) and exendin-4(1-31). Theinsulinotropic property of a compound may be determined by in vivo or invitro assays well known in the art. For instance, the compound may beadministered to an animal and monitoring the insulin concentration overtime. Insulinotropic analogues of GLP-1(1-37) and exendin-4(1-39) referto the respective molecules wherein one or more of the amino acidsresidues have been exchanged with other amino acid residues and/or fromwhich one or more amino acid residues have been deleted and/or fromwhich one or more amino acid residues have been added with the provisothat said analogue either is insulinotropic or is a prodrug of aninsulinotropic compound. Examples of insulinotropic analogues of GLP-1(1-37) are e.g. Met⁸-GLP-1 (7-37) wherein the alanine in position 8 hasbeen replaced by methionine and the amino acid residues in position 1 to6 have been deleted, and Arg³⁴-GLP-1 (7-37) wherein the valine inposition 34 has been replaced with arginine and the amino acid residuesin position 1 to 6 have been deleted. An example of an insulinotropicanalogue of exendin-4(1-39) is Ser²Asp³-exendin-4(1-39) wherein theamino acid residues in position 2 and 3 have been replaced with serineand aspartic acid, respectively (this particular analogue also beingknown in the art as exendin-3). Insulinotropic derivatives of GLP-1(1-37), exendin-4(1-39) and analogues thereof are what the personskilled in the art considers to be derivatives of these peptides, i.e.having at least one substituent which is not present in the parentpeptide molecule with the proviso that said derivative either isinsulinotropic or is a prodrug of an insulinotropic compound. Examplesof substituents are amides, carbohydrates, alkyl groups and lipophilicsubstituents. Examples of insulinotropic derivatives of GLP-1 (1-37),exendin-4(1-39) and analogues thereof are GLP-1 (7-36)-amide, Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1 (7-37) andTyr³¹-exendin-4(1-31)-amide. Further examples of GLP-1 (1-37),exendin-4(1-39), insulinotropic fragments thereof, insulinotropicanalogues thereof and insulinotropic derivatives thereof are describedin WO 98/08871, WO 99/43706, U.S. Pat. No. 5,424,286 and WO 00/09666.

In another aspect of the present invention, the present compounds areadministered in combination with more than one of the above-mentionedcompounds e.g. in combination with metformin and a sulphonylurea such asglyburide; a sulphonylurea and acarbose; nateglinide and metformin;acarbose and metformin; a sulfonylurea, metformin and troglitazone;insulin and a sulfonylurea; insulin and metformin; insulin, metforminand a sulfonylurea; insulin and troglitazone; insulin and lovastatin;etc.

It should be understood that any suitable combination of the compoundsaccording to the invention with diet and/or exercise, one or more of theabove-mentioned compounds and optionally one or more other activesubstances are considered to be within the scope of the presentinvention. In one embodiment of the present invention, thepharmaceutical composition according to the present invention comprisese.g. a compound of the invention in combination with metformin and asulphonylurea such as glyburide; a compound of the invention incombination with a sulphonylurea and acarbose; nateglinide andmetformin; acarbose and metformin; a sulfonylurea, metformin andtroglitazone; insulin and a sulfonylurea; insulin and metformin;insulin, metformin and a sulfonylurea; insulin and troglitazone; insulinand lovastatin; etc.

Pharmaceutical Compositions

The compounds of the present invention may be administered alone or incombination with pharmaceutically acceptable carriers or excipients, ineither single or multiple doses. The pharmaceutical compositionsaccording to the invention may be formulated with pharmaceuticallyacceptable carriers or diluents as well as any other known adjuvants andexcipients in accordance with conventional techniques such as thosedisclosed in Remington: The Science and Practice of Pharmacy, 19^(th)Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

The pharmaceutical compositions may be specifically formulated foradministration by any suitable route such as the oral, rectal, nasal,pulmonary, topical (including buccal and sublingual), transdermal,intracisternal, intraperitoneal, vaginal and parenteral (includingsubcutaneous, intramuscular, intrathecal, intravenous and intradermal)route, the oral route being preferred. It will be appreciated that thepreferred route will depend on the general condition and age of thesubject to be treated, the nature of the condition to be treated and theactive ingredient chosen.

Pharmaceutical compositions for oral administration include solid dosageforms such as hard or soft capsules, tablets, troches, dragees, pills,lozenges, powders and granules. Where appropriate, they can be preparedwith coatings such as enteric coatings or they can be formulated so asto provide controlled release of the active ingredient such as sustainedor prolonged release according to methods well known in the art.

Liquid dosage forms for oral administration include solutions,emulsions, aqueous or oily suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration includesterile aqueous and non-aqueous injectable solutions, dispersions,suspensions or emulsions as well as sterile powders to be reconstitutedin sterile injectable solutions or dispersions prior to use. Depotinjectable formulations are also contemplated as being within the scopeof the present invention.

Other suitable administration forms include suppositories, sprays,ointments, cremes, gels, inhalants, dermal patches, implants etc.

A typical oral dosage is in the range of from about 0.001 to about 100mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kgbody weight per day, and more preferred from about 0.05 to about 10mg/kg body weight per day administered in one or more dosages such as 1to 3 dosages. The exact dosage will depend upon the frequency and modeof administration, the sex, age, weight and general condition of thesubject treated, the nature and severity of the condition treated andany concomitant diseases to be treated and other factors evident tothose skilled in the art.

The formulations may conveniently be presented in unit dosage form bymethods known to those skilled in the art. A typical unit dosage formfor oral administration one or more times per day such as 1 to 3 timesper day may contain from 0.05 to about 1000 mg, preferably from about0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200mg. For parenteral routes such as intravenous, intrathecal,intramuscular and similar administration, typically doses are in theorder of about half the dose employed for oral administration.

The compounds of this invention are generally utilized as the freesubstance or as a pharmaceutically acceptable salt thereof. Examples arean acid addition salt of a compound having the utility of a free baseand a base addition salt of a compound having the utility of a freeacid. The term “pharmaceutically acceptable salts” refers to non-toxicsalts of the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid or byreacting the acid with a suitable organic or inorganic base. When acompound according to the present invention contains a free base suchsalts are prepared in a conventional manner by treating a solution orsuspension of the compound with a chemical equivalent of apharmaceutically acceptable acid. When a compound according to thepresent invention contains a free acid such salts are prepared in aconventional manner by treating a solution or suspension of the compoundwith a chemical equivalent of a pharmaceutically acceptable base.Physiologically acceptable salts of a compound with a hydroxy groupinclude the anion of said compound in combination with a suitable cationsuch as sodium or ammonium ion. Other salts which are notpharmaceutically acceptable may be useful in the preparation ofcompounds of the present invention and these form a further aspect ofthe present invention.

For parenteral administration, solutions of the novel compounds of theformula (I) in sterile aqueous solution, aqueous propylene glycol orsesame or peanut oil may be employed. Such aqueous solutions should besuitably buffered if necessary and the liquid diluent first renderedisotonic with sufficient saline or glucose. The aqueous solutions areparticularly suitable for intravenous, intramuscular, subcutaneous andintraperitoneal administration. The sterile aqueous media employed areall readily available by standard techniques known to those skilled inthe art.

Suitable pharmaceutical carriers include inert solid diluents orfillers, sterile aqueous solution and various organic solvents. Examplesof solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc,gelatine, agar, pectin, acacia, magnesium stearate, stearic acid andlower alkyl ethers of cellulose. Examples of liquid carriers are syrup,peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines,polyoxyethylene and water. Similarly, the carrier or diluent may includeany sustained release material known in the art, such as glycerylmonostearate or glyceryl distearate, alone or mixed with a wax. Thepharmaceutical compositions formed by combining the novel compounds ofthe present invention and the pharmaceutically acceptable carriers arethen readily administered in a variety of dosage forms suitable for thedisclosed routes of administration. The formulations may conveniently bepresented in unit dosage form by methods known in the art of pharmacy.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules or tablets, eachcontaining a predetermined amount of the active ingredient, and whichmay include a suitable excipient. Furthermore, the orally availableformulations may be in the form of a powder or granules, a solution orsuspension in an aqueous or non-aqueous liquid, or an oil-in-water orwater-in-oil liquid emulsion. Compositions intended for oral use may beprepared according to any known method, and such compositions maycontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents, and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets may contain the active ingredient in admixturewith non-toxic pharmaceutically-acceptable excipients which are suitablefor the manufacture of tablets. These excipients may be for example,inert diluents, such as calcium carbonate, sodium carbonate, lactose,calcium phosphate or sodium phosphate; granulating and disintegratingagents, for example corn starch or alginic acid; binding agents, forexample, starch, gelatin or acacia; and lubricating agents, for examplemagnesium stearate, stearic acid or talc. The tablets may be uncoated orthey may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate may be employed. They mayalso be coated by the techniques described in U.S. Pat. Nos. 4,356,108;4,166,452; and 4,265,874, incorporated herein by reference, to formosmotic therapeutic tablets for controlled release. Formulations fororal use may also be presented as hard gelatin capsules where the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or a soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions may contain the active compounds in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatidesuch as lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more coloring agents,one or more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as a liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active compound inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, flavoring, and coloringagents may also be present. The pharmaceutical compositions of thepresent invention may also be in the form of oil-in-water emulsions. Theoily phase may be a vegetable oil, for example, olive oil or arachisoil, or a mineral oil, for example a liquid paraffin, or a mixturethereof. Suitable emulsifying agents may be naturally-occurring gums,for example gum acacia or gum tragacanth, naturally-occurringphosphatides, for example soy bean, lecithin, and esters or partialesters derived from fatty acids and hexitol anhydrides, for examplesorbitan monooleate, and condensation products of said partial esterswith ethylene oxide, for example polyoxyethylene sorbitan monooleate.The emulsions may also contain sweetening and flavoring agents. Syrupsand elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known methods using suitable dispersing orwetting agents and suspending agents described above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conveniently employed as solvent or suspending medium. For thispurpose, any bland fixed oil may be employed using synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

The compositions may also be in the form of suppositories for rectaladministration of the compounds of the present invention. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will thus melt in the rectum torelease the drug. Such materials include cocoa butter and polyethyleneglycols, for example.

For topical use, creams, ointments, jellies, solutions of suspensions,etc., containing the compounds of the present invention arecontemplated. For the purpose of this application, topical applicationsshall include mouth washes and gargles.

The compounds of the present invention may also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes may beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

In addition, some of the compounds of the present invention may formsolvates with water or common organic solvents. Such solvates are alsoencompassed within the scope of the pre-sent invention.

Thus, in a further embodiment, there is provided a pharmaceuticalcomposition comprising a compound according to the present invention, ora pharmaceutically acceptable salt, solvate, or prodrug thereof, and oneor more pharmaceutically acceptable carriers, excipients, or diluents.

If a solid carrier is used for oral administration, the preparation maybe tableted, placed in a hard gelatine capsule in powder or pellet formor it can be in the form of a troche or lozenge. The amount of solidcarrier will vary widely but will usually be from about 25 mg to about 1g. If a liquid carrier is used, the preparation may be in the form of asyrup, emulsion, soft gelatine capsule or sterile injectable liquid suchas an aqueous or non-aqueous liquid suspension or solution.

A typical tablet that may be prepared by conventional tablettingtechniques may contain:

Core: Active compound (as free compound or salt 5.0 mg thereof) LactosumPh. Eur. 67.8 mg  Cellulose, microcryst. (Avicel) 31.4 mg Amberlite ®IRP88* 1.0 mg Magnesii stearas Ph. Eur. q.s. Coating:Hydroxypropyl methylcellulose approx.   9 mg Mywacett 9-40 T** approx.0.9 mg *Polacrillin potassium NF, tablet disintegrant, Rohm and Haas.**Acylated monoglyceride used as plasticizer for film coating.

If desired, the pharmaceutical composition of the present invention maycomprise a compound according to the present invention in combinationwith further active substances such as those described in the foregoing.

The present invention also provides a method for the synthesis ofcompounds useful as intermediates in the preparation of compounds offormula (I) along with methods for the preparation of compounds offormula (I). The compounds can be prepared readily according to thefollowing reaction Schemes (in which all variables are as definedbefore, unless so specified) using readily available starting materials,reagents and conventional synthesis procedures. In these reactions, itis also possible to make use of variants which are themselves known tothose of ordinary skill in this art, but are not mentioned in greaterdetail.

Pharmacological Methods

Glucokinase Activity Assay (I)

Glucokinase activity is assayed spectrometrically coupled to glucose6-phosphate dehydrogenase to determine compound activation ofglucokinase. The final assay contains 50 mM Hepes, pH 7.1, 50 mM KCl, 5mM MgCl₂, 2 mM dithiothreitol, 0.6 mM NADP, 1 mM ATP, 0.195 μM G-6-Pdehydrogenase (from Roche, 127 671), 15 nM recombinant humanglucokinase. The glucokinase is human liver glucokinase N-terminallytruncated with an N-terminal His-tag ((His)₈-VEQILA . . . Q466) and isexpressed in E. coli as a soluble protein with enzymatic activitycomparable to liver extracted GK.

The purification of His-tagged human glucokinase (hGK) was performed asfollows: The cell pellet from 50 ml E. coli culture was resuspended in 5ml extraction buffer A (25 mM HEPES, pH 8.0, 1 mM MgCl₂, 150 mM NaCl, 2mM mercaptoethanol) with addition of 0.25 mg/ml lysozyme and 50 μg/mlsodium azide. After 5 minutes at room temperature 5 ml of extractionbuffer B (1.5 M NaCl, 100 mM CaCl₂, 100 mM MgCl₂, 0.02 mg/ml DNase 1,protease inhibitor tablet (Complete® 1697498): 1 tablet pr. 20 mlbuffer) was added. The extract was then centrifugated at 15,000 g for 30minutes. The resulting supernatant was loaded on a 1 ml Metal ChelateAffinity Chromatography (MCAC) Column charged with Ni²⁺. The column iswashed with 2 volumes buffer A containing 20 mM imidazole and the boundhis-tagged hGK is subsequently eluted using a 20 minute gradient of 20to 500 mM imididazol in buffer A. Fractions are examined usingSDS-gel-electrophoresis, and fractions containing hGK (MW: 52 KDa) arepooled. Finally a gelfiltration step is used for final polishing andbuffer exchange. hGK containing fractions are loaded onto a Superdex 75(16/60) gelfiltration column and eluted with Buffer B (25 mM HEPES, pH8.0, 1 mM MgCl₂, 150 mM NaCl, 1 mM Dithiothreitol). The purified hGK isexamined by SDS-gel electrophoresis and MALDI mass spectrometry andfinally 20% glycerol is added before freezing. The yield from 50 ml E.coli culture is generally approximately 2-3 mg hGK with a purity >90%.

The compound to be tested is added into the well in final 2.5% DMSOconcentration in an amount sufficient to give a desired concentration ofcompound, for instance 1, 5, 10, 25 or 50 μM. The reaction starts afterglucose is added to a final concentration of 2, 5, 10 or 15 mM. Theassay uses a 96-well UV plate and the final assay volume used is 200μl/well. The plate is incubated at 25° C. for 5 min and kinetics ismeasured at 340 nm in SpectraMax every 30 seconds for 5 minutes. Resultsfor each compound are expressed as the fold activation of theglucokinase activity compared to the activation of the glucokinaseenzyme in an assay without compound after having been subtracted from a“blank”, which is without glucokinase enzyme and without compound. Thecompounds in each of the Examples exhibits activation of glucokinase inthis assay. A compound, which at a concentration of at or below 30 μMgives 1.5-fold higher glucokinase activity than the result from theassay without compound, is deemed to be an activator of glucokinase.

The glucose sensitivity of the compounds are measured at a compoundconcentration of 10 μM and at glucose concentrations of 5 and 15 mM.

Glucokinase Activity Assay (II)

Determination of Glycogen Deposition in Isolated Rat Hepatocytes:

Hepatocytes are isolated from rats fed ad libitum by a two-stepperfusion technique. Cell viability, assessed by trypan blue exclusion,is consistently greater than 80%. Cells are plated onto collagen-coated96-well plates in basal medium (Medium 199 (5.5 mM glucose) supplementedwith 0.1 μM dexamethasone, 100 units/ml penicillin, 100 mg/mlstreptomycin, 2 mM L-glutamine and 1 nM insulin) with 4% FCS at a celldensity of 30,000 cells/well. The medium is replaced with basal medium 1hour after initial plating in order to remove dead cells. Medium ischanged after 24 hours to basal medium supplemented with 9.5 mM glucoseand 10 nM insulin to induce glycogen synthesis, and experiments areperformed the next day. The hepatocytes are washed twice with prewarmed(37° C.) buffer A (117.6 mM NaCl, 5.4 mM KCl, 0.82 mM Mg₂SO₄, 1.5 mMKH₂PO₄, 20 mM HEPES, 9 mM NaHCO₃, 0.1% w/v HSA, and 2.25 mM CaCl₂, pH7.4 at 37° C.) and incubated in 100 μl buffer A containing 15 mM glucoseand increasing concentrations of the test compound, such as for instance1, 5, 10, 25, 50 or 100 μM, for 180 minutes. Glycogen content ismeasured using standard procedures (Agius, L. et al, Biochem J. 266,91-102 (1990). A compound, which when used in this assay gives ansignificant increase in glycogen content compared to the result from theassay without compound, is deemed to have activity in this assay.

Glucokinase Activity Assay (III)

Stimulation of Insulin Secretion by Glucokinase Activators in INS-1ECells

The glucose responsive β-cell line INS-1E is cultivated as described byAsfari M et al., Endocrinology, 130, 167-178 (1992). The cells are thenseeded into 96 well cell culture plates and grown to a density ofapproximately 5×10⁴ per well. Stimulation of glucose dependent insulinsecretion is tested by incubation for 2 hours in Krebs Ringer Hepesbuffer at glucose concentrations from 2.5 to 15 mM with or withoutaddition of glucokinase activating compounds in concentrations of forinstance 1, 5, 10, 25, 50 or 100 μM, and the supernatants collected formeasurements of insulin concentrations by ELISA (n=4). A compound, whichwhen used in this assay gives an significant increase in insulinsecretion in response to glucose compared to the result from the assaywithout compound, is deemed to have activity in this assay.

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of the presentinvention. For example, effective dosages other than the preferreddosages as set forth herein may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated forglucokinase-deficiency mediated disease(s). Likewise, the specificpharmacological responses observed may vary according to and dependingon the particular active compound selected or whether there are presentpharmaceutical carriers, as well as the type of formulation and mode ofadministration employed, and such expected variations or differences inthe results are contemplated in accordance with the objects andpractices of the present invention.

EXAMPLES

Abbreviations used in the Schemes and Examples are as follows:

d=day(s)

g=gram(s)

h=hour(s)

MHz=mega hertz

L=liter(s)

M=molar

mg=milligram(s)

min=minute(s)

mL=milliliter(s)

mM=millimolar

mmol=millimole(s)

mol=mole(s)

N=normal

ppm=parts per million

i.v.=intravenous

m/z=mass to charge ratio

mp=melting point

MS=mass spectrometry

HPLC=high pressure liquid chromatography

HPLC-MS=high pressure liquid chromatography-mass spectrometry

NMR=nuclear magnetic resonance spectroscopy

p.o.=per oral

R_(t)=retention time

rt=room temperature

s.c.=subcutaneous

TLC=thin layer chromatography

BuOK=Potassium tert-butoxide

Boc=tert-Butyloxcarbonyl

CDI=carbonyldiimidazole

DBU=1,8-Diazabicyclo[5.4.0]-undec-7-en

DCM (CH₂Cl₂)=dichloromethane, methylenechloride

DHOBt=3,4-Dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine

DIC=1,3-Diisopropyl carbodiimide

DCC=1,3-Dicyclohexyl carbodiimide

DIEA=N,N-diisopropylethylamine

DIPEA=N,N-diisopropylethylamine

DMA=N,N-dimethylacetamide

DMAP=4-(N,N-dimethylamino)pyridine

DMF=N,N-dimethylformamide

DMF=N,N-dimethylformamide

DMPU=NN′-dimethylpropyleneurea, 1,3-dimethyl-2-oxohexahydropyrimidine

EDAC=1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride

Et₂O=diethyl ether

EtOAc=ethyl acetate

HMPA=hexamethylphosphoric acid triamide

HOBt=N-Hydroxybenzotriazole

HOAt=7-Aza-1-Hydroxybenzotriazole

LAH, (LiAlH₄)=Lithiumaluminium hydride

LDA=lithium diisopropylamide

MeCN=acetonitrile

MeOH=methanol

NMP=N-methylpyrrolidin-2-one

NaH=Sodium Hydride

NH₂OH=Hydroxylamine

PyBroP=Bromotrispyrrolidinophosphonium hexafluorophosphate

TEA (Et₃N)=triethylamine

TFA=trifluoroacetic acid

THF=tetrahydrofuran

CDCl₃=deuterio chloroform

CD₃OD=tetradeuterio methanol

DMSO-d₆=hexadeuterio dimethylsulfoxide

HPLC-MS

The RP-analysis was performed on an Agilent HPLC system (1100 degasser,1100 pump, 1100 injector and a 1100 DAD) fitted with an Agilent MSdetector system Model SL (MW 0-3000) and a S.E.D.E.R.E Model Sedex 75ELS detector system using a Waters X-terra MS C18 column (5 μm, 3.0mm×50 mm) with gradient elution, 5% to 100% solvent B (0.05% TFA inacetonitrile) in solvent A (0.05% TFA in water) within 6.75 min, 1.5mL/min.

Preparative HPLC

The RP-purification was performed on a Gilson system (3 Gilson 306pumps, Gilson 170 DAD detector and a Gilson 215 liquidhandler) using aWaters X-terra RP (10 μm, 30 mm×150 mm) with gradient elution, 5% to 95%solvent B (0.05% TFA in acetonitrile) in solvent A (0.05% TFA in water)within 15 min, 40 mL/min, detection at 210 nm, temperature rt. Thepooled fractions are either evaporated to dryness in vacuo, orevaporated in vacuo until the acetonitrile is removed, and then frozenand freeze dried.

NMR

Proton NMR spectra were recorded at ambient temperature using a BruckerAvance DPX 400 (400 MHz) with tetramethylsilane as an internal standard.Chemical shifts (δ) are given in ppm

General

The following examples and general procedures refer to intermediatecompounds and final products for general formula (I) identified in thespecification and in the synthesis schemes. The preparation of thecompounds of general formula (I) of the present invention is describedin detail using the following examples. Occasionally, the reaction maynot be applicable as described to each compound included within thedisclosed scope of the invention. The compounds for which this occurswill be readily recognised by those skilled in the art. In these casesthe reactions can be successfully performed by conventionalmodifications known to those skilled in the art, which is, byappropriate protection of interfering groups, by changing to otherconventional reagents, or by routine modification of reactionconditions. Alternatively, other reactions disclosed herein or otherwiseconventional will be applicable to the preparation of the correspondingcompounds of the invention. In all preparative methods, all startingmaterials are known or may be prepared by a person skilled in the art inanalogy with the preparation of similar known compounds or by theGeneral procedures A through K described herein.

The structures of the compounds are confirmed by either by nuclearmagnetic resonance (NMR) and/or by HPLS-MS.

General Procedure (A)

Compounds of the formula (Ia) according to the invention wherein R¹, R²and A are as defined for formula (I) can be prepared as outlined below:

Step 1.

The aminoheterocycle (NH₂A) (III) wherein A is as defined for formula(I), can be converted using standard literature procedures (for exampleWO 2004/002481) to an acyl imidazonium intermediate with carbonyldiimidazole (CDI) or an equivalent of this in a solvent such asdichloromethane, dichloroethane, tetrahydrofuran, or DMF. Treatment withR¹R²NH (II), wherein R¹ and R² are as defined above, gives the compoundof formula (Ia). The aminoheterocycle (NH₂A) or secondary amine (R¹R²NH)can be either commercially available compounds or compounds that can beprepared following procedures described in the literature or prepared asdescribed in the relevant example and general procedures.

Step 2.

In some cases it might be more convenient to generate the finalsubstituents on R¹, R² and A after the urea formation. If in example thesubstituent on A in formula (Ia) contains an ester functionality thiscan be hydrolysed to the corresponding carboxylic acid using standardconditions for hydrolysis of esters. Suitable bases for the hydrolysisare NaOH and LiOH or equivalents of these in solvents like dioxane, THF,EtOH, MeOH and water or mixtures of these. The reactions can beperformed at room temperature or at elevated temperatures.

Other examples are described in general procedure I and J.

General Procedure (B)

The desired amines R¹R²NH described in General procedure (A) can inexample be prepared by a reductive amination with a suitable primaryamine and a ketone or an aldehyde. The reaction can be performed inTHF-MeOH or similar solvents in the presence of molecular sieves (4 Å)or with 10% AcOH, using NaBH₃CN or suitable equivalents of this asreducing agent. The primary amine, ketone and aldehyde can be eithercommercially available compounds or compounds that can be preparedfollowing procedures described in the literature or prepared asdescribed in the relevant example and general procedures.

General Procedure (C)

In case the primary amines (R¹NH₂) are not sufficiently reactive toundergo reductive amination (general procedure B), the desired secondaryamines can be prepared by initial formation of a secondary amide using aprimary amine and an acid chloride or an equivalent thereof andsubsequent reduction of the amide. The amide reduction can be performedin THF or similar solvents using borane or suitable equivalents. Theprimary amine and the acid chloride can be either commercially availablecompounds or compounds that can be pre-pared following proceduresdescribed in the literature or prepared as described in the relevantexample and general procedures.

General Procedure (D)

Preparation of trans-alkoxymethylcyclohexylamine and the Like

The carbonyl group of 4-oxo-cyclohexanone carboxylic acid methyl estercan be protected as ketal by reaction with ethylene glycol in benzenewith azeotropic removal of water. The ester group can then be reducedwith lithium aluminium hydride in a suitable solvent such as diethylether or tetrahydrofuran. The alcohol can be alkylated using sodiumhydride and a suitable alkyl halide (R—X, wherein R is an appropriateradical defined according to the invention) in a solvent such astetrahydrofuran or DMF. Ketal deprotection of the product under standardacidic conditions gives the corresponding ketone, which can be convertedto the corresponding oxime upon treatment with hydroxylamine and asuitable base (for example sodium acetate). Reduction of the oxime usingsodium in ethanol affords the trans-4-alkoxymethyl-cyclohexylamine asthe major isomer, which, if necessary can be purified byrecrystallisation of the corresponding HCl salt.

General Procedure (E)

Preparation of trans-4-alkoxy-cyclohexylamine and the Like

2-(trans-4-Hydroxy-cyclohexyl)-isoindole-1,3-dione (Glennon et al. J.Med. Chem. 1996, 39, 1, 314-322) can be alkylated with an alkylatingagent such as R-halides (wherein R is a radical defined according to theinvention) or an equivalent of this using a base such as NaH, potassiumtert-butoxid, DBU or the like in a solvent like DMF, NMP, DMSO, THF attemperatures from −10 to 120° C. Deprotection of thetrans-4-alkoxy-cyclohexyl-isoindole-1,3-dione can be achieve usinghydrazine in ethanol at room temperature or at elevated temperatures.

General Procedure (F)

Preparation of trans-4-alkyl-cyclohexylamines and the Like

A 4-substituted cyclohexanone (wherein R is a radical defined accordingto the invention) can be converted to the corresponding oxime upontreatment with hydroxylamine hydrochloride and a suitable base such assodium acetate in a solvent mixture such as water/MeOH at elevatedtemperature. Reduction of the oxime using sodium in ethanol at elevatedtemperatures affords the trans-4-alkyl/aryl-cyclohexylamine as the majorisomer, which, if necessary can be purified by recrystallisation of thecorresponding HCl salt.

General Procedure (G)

Preparation of alkyl-(trans-4-alkyl-cyclohexyl)-amine and the Like

To a mixture of a 4-trans-substituted cyclohexylamine (wherein R is aradical defined according to the invention), hydrochloride in DMF, NMP,MeCN or a similar solvent was added potassium carbonate, NaOH or anequivalent of such a base. The alkyl halide (wherein R¹ is definedaccording to the invention) was added and the reaction mixture washeated until completion of the reaction. The crude product can be usedas such for subsequent reactions or alternatively it can be purifiedbefore further reactions.

General Procedure (H)

Preparation of 2-Amino-thiazole-5-sulfonic acid amides

A mixture of an amine, protected amino acid or the like (wherein R andR′ are radicals defined according to the invention) is reacted with2-acetylamino-thiazole-5-sulfonyl chloride prepared as described in J.Am. Chem. Soc, 1947, 69, 2063) in the presence of a base such as DIPEAin DCM. N-Deacetylation of the intermediate can be achieved upon heatingin the presence of HCl in dioxane/EtOH to give the requiredsulfonamido-2-aminothiazole.

General Procedure (I)

5-Thiosubstituted aminothiazole-urea derivatives can be oxidized with anoxidizing agent such as m-chloroperbenzoic acid in DCM, with oxone andmontmorillonite in water/DCM or with hydrogenperoxide in AcOH (J. Org.Chem. 1965, 2688-2691) to give the corresponding sulfonyl derivatives.

General Procedure (J)

3-(2-Amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl estercan be prepared from 5-thiocyanato-thiazol-2-ylamine by treatment withsodium borohydride in MeOH followed by addition of3-bromo-2,2-dimethyl-propionic acid. After aqueous work up theintermediate acid can be treated with HCl in EtOH to give the3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethylpropionic acid ethyl ester.

The aminothiazole ester can be coupled to the final urea derivativefollowing the general procedure (A).

General Procedure (K)

The hydroxypropyl- and hydroxyethylderivatives, prepared as described inthe synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid and{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid, can be treated with mesyl chloride and DIPEA in DCM to obtain thecorresponding mesylate. This can be treated with a thiol like thiophenolog phenyl-methanethiol in acetone using potassium carbonate as base.After removal of the Boc group the secondary amine can be coupled andhydrolysed using the methods described in general procedure (A) to givethe final urea thiazole.

Example 1[2-(3-Cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid

(General Procedure (A) and (B))

(Reductive Amination:

Preparation of Cyclohexyl Phenetylamine

Phenethylamine (121 mg, 1.0 mmol) in a 2:1 mixture of THF-MeOH (2 mL)was added cyclohexanone (98 mg, 1.0 mmol) and molecular sieves (4 Å, 80mg). The reaction mixture was shaken for 1 h before NaBH₃CN (126 mg, 2.0mmol) was added. The reaction mixture was shaken for 24 h before it wasfiltered and the filtrate was concentrated in vacuo to give theintermediate cyclohexyl phenetylamine.

Coupling:

Preparation of (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester

5-Bromo-2-aminothiazole (25 g, 96 mmol) and K₂CO₃ (26.5 g, 192 mmol) wassuspended in DMF (50 mL) and stirred to 0° C. Ethyl thioglycolate (11.6mL, 96 mmol) was added during 10 min. The reaction mixture was allowedto reach room temperature and stirred for further 16 h. Addition ofwater (100 mL) and EtOAc (150 mL). Separation of the organic phasefollowed by extraction of the aqueous phase with EtOAc (2×100 mL). Thecombined organic phases were washed with aqueous NaHCO₃ (2000 mL), brine(2×200 mL) and dried (MgSO₄), filtered and evaporated. The crude productwas dissolved in a small amount of DCM and purified by flashchromathography (ISCO 330 g silica column, eluent A: heptane/B: 2% TEAin EtOAc. Gradient from 30% B->100% B.) to give 50-65% pure(2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester as a dark red-brownoil.

¹H NMR (CDCl₃): δ 7.16 (s, 1H), 5.45 (bs, 2H), 4.26 (q, 2H), 3.39 (s,2H), 1.28 (t, 3H).

2-Amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester (218 mg, 1.0 mmol)in DCM (2 mL) was added in sequence CDI (162 mg, 1.0 mmol), DMAP (6 mg,0.05 mmol) and DIPEA (129 mg, 1.0 mmol) and the mixture was stirred for1 h before it was added to the intermediate cyclohexyl phenethylamine.The reaction mixture was stirred for 16 h before the volatiles wereremoved in vacuo.

Hydrolysis:

MeOH (1 mL) was added followed by NaOH (0.50 mL 10 N, 5 mmol) and shakenfor 16 h before the mixture was quenced with AcOH (0.286 mL, 5 mmol),whereupon MeOH (0.5 mL) and DMSO (0.5 mL) was added. The mixture waspurified on preparative HPLC to give 120 mg (29%) of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (s, 1H), 7.35-7.25 (m, 4H), 7.24-7.19(m, 1H), 4.10-3.95 (m, 1H), 3.5 (s, 2H), 3.45-3.35 (m, 2H), 2.85-2.75(m, 2H), 1.80-1.70 (m, 2H), 1.65-1.40 (m, 5H), 1.40-1.25 (m, 2H),1.18-1.05 (m, 1H).

HPLC-MS: m/z=420 (M+1), R_(t)=2.1 min

Example 2 [2-(3-Butyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from n-butylamine, cyclohexanone and2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (s, 1H), 4.02-3.90 (m, 1H), 3.49 (s,2H), 3.25-3.15 (m, 2H), 1.8-1.0 (m, 14H), 0.89 (t, 3H).

HPLC-MS: m/z=372, R_(t)=2.0 min

Example 3{2-[3-Cyclohexyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from 3-methyl-butylamine, cyclohexanone and2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 4.02-3.90 (m, 1H), 3.49 (s,2H), 3.28-3.18 (m, 2H), 1.80-1.00 (m, 13H), 0.90 (d, 6H).

HPLC-MS: m/z=386, R_(t)=2.1 min

Example 4{2-[3-Cyclohexyl-3-(2,2-dimethyl-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from 3,3-dimethyl-propylamine, cyclohexanone and2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 3.49 (s, 2H), 3.19 (s, 2H),2.08-1.85 (m, 2H), 1.80-1.62 (m, 4H), 1.61-1.52 (m, 1H), 1.30-1.00 (m,3H), 0.91 (s, 9H).

HPLC-MS: m/z=386, R_(t)=2.1 min

Example 5{2-[3-(2-Cyclohex-1-enyl-ethyl)-3-cyclohexyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from 2-(1-cyclohexenyl)-ethylamine, cyclohexanone and2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.41 (s, 1H), 4.42 (bs, 1H), 4.0-3.9 (m,1H), 3.48 (s, 2H), 3.38-3.22 (m, 2H), 2.15-2.05 (m, 2H), 2.0-1.9 (m,4H), 1.80-1.00 (m, 12H)

HPLC-MS: m/z=424, R_(t)=2.3 min

Example 6[2-(3-Bicyclo[2.2.1]hept-2-ylmethyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from c-bicyclo[2.2.1]hept-2-yl-methylamine, cyclohexanone and2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 3.9-3.7 (m, 1H), 3.49 (s, 2H),3.40-3.25 (d, 2H), 2.20-1.95 (m, 3H), 1.80-0.70 (m, 20H).

HPLC-MS: m/z=424, R_(t)=2.3 min

Example 7[2-(3-Bicyclo[2.2.1]hept-5-en-2-ylmethyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from c-bicyclo[2.2.1]hept-5-en-2-yl-methylamine, cyclohexanone and2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) (mixture of two isomers) δ 7.40 (s, 1H),6.24-6.19 (m, 0.7H), 6.10-6.03 (m, 1.3H), 3.95-3.70 (m, 1H), 3.48 (s,2H), 3.10-2.88 (m, 2H), 2.80-2.70 (m, 2H), 2.35-2.25 (m, 1H), 1.87-1.00(m, 11.3H), 0.65-0.55 (m, 0.7H)

HPLC-MS: m/z=422, R_(t)=2.2 min

Example 8{2-[3-Cyclohexyl-3-(2-cyclohexyl-ethyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from 2-cyclohexylethylamine, cyclohexanone and2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=426 R_(t)=2.4 min

Example 93-[2-(3-Cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-propionicacid

Preparation of 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethylester

5-Bromo-2-aminothiazole (25 g, 96 mmol) in DMF (150 mL) was added K₂CO₃(26.5 g, 192 mmol) and the mixture was purged with N₂ for 5 min. Themixture was cooled to 0° C. on an ice bath before 3-mercaptopropionicacid ethyl ester (12.9 g, 96 mmol) was added dropwise over the course of30 min. The reaction mixture was stirred for 16 hours before water (400mL) was added. The aqueous mixture was extracted with Et₂O (1×500 mL,2×250 mL). The combined organic phases was washed with saturated NH₄Cl(3×150 mL), dried (MgSO₄). The solvent was removed in vacuo to give adark residue which was purified by column chromatography (SiO₂,EtOAc-heptane (1:1)). The solvent was removed in vacuo to give 11 g(49%) of the desired compound.

¹H NMR (400 MHz, CDCl₃) δ 7.1 (s, 1H), 5.2 (bs, 2H), 4.2 (q, 2H), 2.8(t, 2H), 2.6 (t, 2H), 1.3 (t, 3H).

3-[2-(3-Cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-propionicacid was prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from 2-phenethylamine, cyclohexanone and2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.41 (s, 1H), 7.45-7.15 (m, 5H), 4.10-3.95(m, 1H), 3.50-3.40 (m, 2H), 2.87 (t, 2H), 2.78 (m, 2H), 2.5 (t, 2H),1.8-1.0 (m, 10H)

HPLC-MS: m/z=386, R_(t)=2.1 min

Example 103-[2-(3-Butyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-propionic acid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from n-butylamine, cyclohexanone and2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 4.05-3.90 (m, 1H), 3.2 (t,2H), 2.83 (t, 2H), 2.50 (t, 2H), 1.80-1.00 (m, 14H), 0.89 (t, 3H)

HPLC-MS: m/z=434, R_(t)=2.2 min

Example 113-{2-[3-Cyclohexyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from 3-methylbutylamine, cyclohexanone and2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 4.04-3.92 (m, 1H), 3.28-3.18(m, 2H), 2.83 (t, 2H), 2.50 (t, 2H), 1.80-1.00 (m, 13H), 0.90 (d, 6H)

HPLC-MS: m/z=400, R_(t)=2.2 min

Example 123-{2-[3-(trans-4-Methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from phenyl acetaldehyde, trans-4-methylcyclohexylamine hydrochloride(prepared via the methode described in J. Med. Chem. 1971, vol 14, p.610) and 2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. Thehydrochloride was added one equivalent DIPEA prior to the reaction.

¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (s, 1H), 7.35-7.25 (m, 5H), 4.08-3.92(m, 1H), 3.50-3.35 (m, 2H), 2.87 (t, 2H), 2.82-2.72 (m, 2H), 1.80-0.95(m, 9H), 0.88 (d, 3H).

HPLC-MS: m/z=448, R_(t)=2.3 min

Example 133-{2-[3-Butyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from butyraldehyde, trans-4-methylcyclohexylamine hydrochloride and2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. Thehydrochloride was added one equivalent DIPEA prior to the reaction.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 4.02-3.90 (m, 2H), 3.25-3.15(m, 2H), 2.83 (t, 2H), 2.50 (t, 2H), 1.75-0.95 (m, 13H), 0.92-0.82 (m,6H)

HPLC-MS: m/z=400, R_(t)=2.3 min

Example 143-{2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from isovaleraldehyde, trans-4-methylcyclohexylamine hydrochloride and2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. Thehydrochloride was added one equivalent DIPEA prior to the reaction.

¹H NMR (400 MHz, CDCl₃) δ 11.2 (bs, 1H), 7.28 (s, 1H), 3.25 (m, 2H),3.00 (m, 2H), 2.75 (m, 2H), 2.00-1.00 (m, 13H), 0.95-0.87 (m, 9H).

HPLC-MS: m/z=414, R_(t)=2.4 min

Example 153-{2-[3-(2-Cyclohex-1-enyl-ethyl)-3-cyclohexyl-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from 2-(1-cyclohexenyl)ethylamine hydrochloride, cyclohexanone and2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. Thehydrochloride was added one equivalent DIPEA prior to the reaction.

HPLC-MS: m/z=439, R_(t)=2.5 min

Example 16{2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from 4-trans-methyl-cyclohexylamine hydrochloride, isovaleraldehyde and2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. The hydrochloridewas added one equivalent DIPEA prior to the reaction.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 4.00-3.95 (m, 1H), 3.48 (s,2H), 3.25-3.18 (m, 2H), 1.73-1.65 (m, 2H), 1.65-1.44 (m, 5H), 1.40-1.25(m, 3H), 1.14-1.00 (m, 2H), 0.92-0.84 (m, 9H).

HPLC-MS: m/z=435, R_(t)=2.3 min

Example 17{2-[3-(trans-4-Methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from 4-trans-methyl-cyclohexylamine hydrochloride, phenylacetaldehydeand 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. Thehydrochloride was added one equivalent DIPEA prior to the reaction.

¹H NMR (400 MHz, DMSO-d₆) δ 12 (bs, 1H), 7.42 (s, 1H), 7.35-7.25 (m,4H), 7.23-7.18 (m, 1H), 4.05-3.95 (m, 1H), 3.50 (s, 2H), 3.45-3.35 (m,2H), 2.82-2.75 (m, 2H), 1.72-1.65 (m, 2H), 1.62-1.50 (m, 4H), 1.40-1.30(1H), 1.12-1.00 (m, 2H), 0.87 (d, 3H)

HPLC-MS: m/z=400, R_(t)=2.3 min

Example 18{2-[3-(2-Cyclohex-1-enyl-ethyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from 4-trans-methyl-cyclohexylamine hydrochloride,cyclohexen-1-yl-acetaldehyde (Prepared according to the procedure givenin Oppolzer, W. et al. Tetrahedron, 1985, 41, 17, 3497-3509) and2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. The hydrochloridewas added one equivalent DIPEA prior to the reaction.

¹H NMR (400 MHz, DMSO-d₆) δ 12.5 (bs, 1H), 7.40 (s, 1H), 5.42 (s, 1H),3.48 (s, 2H), 2.12-2.05 (m, 2H), 1.98-1.92 (m, 4H), 1.72-1.65 (m, 2H),1.64-1.45 (m, 9H), 1.40-1.25 (m, 2H), 1.15-1.00 (m, 2H), 0.88 (d, 3H).

HPLC-MS: m/z=438, R_(t)=2.4 min

Example 19{2-[3-(3-Methyl-but-2-enyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from 4-trans-methyl-cyclohexylamine hydrochloride, 3-methyl-but-2-enaland 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. Thehydrochloride was added one equivalent DIPEA prior to the reaction.

¹H NMR (400 MHz, CDCl₃) δ 7.25 (s, 1H), 5.12-5.05 (m, 1H), 4.15-3.95 (m,1H), 3.92 (d, 2H), 3.32 (s, 2H), 1.80-1.70 (m, 3H), 1.70 (s, 6H),1.55-1.42 (m, 2H), 1.40-1.24 (m, 2H), 1.20-1.05 (m, 2H), 0.90 (d, 3H).

HPLC-MS: m/z=398, R_(t)=2.1 min

Example 203-{2-[3-(3-Methyl-but-2-enyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from 4-trans-methyl-cyclohexylamine hydrochloride, 3-methyl-but-2-enaland 2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. Thehydrochloride was added one equivalent DIPEA prior to the reaction.

¹H NMR (400 MHz, CDCl₃) δ 7.25 (s, 1H), 5.15-5.05 (m, 1H), 3.92 (d, 2H),3.05-2.95 (m, 2H), 2.75-2.68 (t, 2H), 1.90-1.80 (m, 2H), 1.80-1.70 (m,2H), 1.70 (s, 3H), 1.68 (s, 3H) 1.60-1.40 (m, 3H), 1.40-1.20 (m, 3H),0.91 (d, 3H).

HPLC-MS: m/z=412, R_(t)=2.2 min

Example 21{2-[3-(4-trans-Ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

(General Procedure (F), (G), (B) and (A, Step 2))

Preparation of trans-4-alkyl-cyclohexylamines

Sodium (45 g, 1.96 mol) was slowly added to a solution of4-ethylcyclohexanone oxime (33 g, 0.23 mol) (prepared according to lift.R. O. Hutchins et al. J. Org. Chem. 60 (1995) 7396-7405)) in 99.9%ethanol (500 mL) while keeping the temperature below 65° C. The reactionmixture was heated at reflux temperature for 11/2 h and then stirred atroom temperature for further 16 h. A mixture of water (500 mL) andethanol (100 mL) was added and the mixture was extracted with diethylether (3×250 mL). The combined organic phases was washed with brine (150mL), dried over anhydrous magnesium sulphate and evaporated to dryness.The residue was dissolved in ethanol (100 mL), pH was adjusted toapprox. 3 with 4 N hydrochloric acid (60 mL) and the solution wasevaporated to dryness in vacuo to give crude ethylcyclohexylamine. Theproduct was purified by recrystallization from ethanol/acetonitrile(4:1) to give 4-trans-ethylcyclohexylamine, hydrochloride as whitecrystals.

Preparation of alkyl-(trans-4-alkyl-cyclohexyl)-amine

To a mixture of 4-trans-ethylcyclohexylamine, hydrochloride (1.5 g, 9.2mmol), dry DMF (40 mL), and potassium carbonate (3.75 g, 27.2 mmol) wasadded 1-bromo-3-methylbutane (1.125 mL, 9.4 mmol). The mixture washeated at 55° C. for 24 h, filtered, and evaporated to dryness in vacuoafter adjusting the pH to 3-4 by adding hydrogen chloride in diethylether. The crude product of(4-trans-ethylcyclohexyl)-(3-methylbutyl)-amine, hydrochloride was usedin the next step without further purification.

Coupling:

To a solution of (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester(200 mg, 0.92 mmol) in dry THF (2 mL) was added CDI (152 mg, 0.92 mmol)and DMAP (50 mg, 0.046 mmol). The mixture was stirred at roomtemperature for 11/2 h after which 4-trans-ethylcyclohexylamine,hydrochloride (220 mg, 0.94 mmol) in THF (3 mL) and DIPEA (0.83 mL, 4.77mmol) were added. Stirring was continued overnight at room temperature.The reaction mixture was evaporated to dryness in vacuo and purified onsilica gel (gradient, from heptane:ethyl acetate (9:1) to heptane:ethylacetate (4:6)) to give 86 mg (yield: 21%) of ethyl{2-[3-(4-trans-ethylcyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetate.

Hydrolysis:

To a solution of ethyl{2-[3-(4-trans-ethylcyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetate(86 mg, 0.195 mmol) in dioxan (1 mL) was added 1 N sodium hydroxide(0.75 mL). The mixture was stirred for 4 h at room temperature. 2 Nhydrochloric acid (0.38 mL) was added and the mixture was evaporatedpartly in vacuo to remove dioxan The residue was stirred with water anddried in vacuo to give the title compound as white crystals

¹H NMR (400 MHz, CDCl₃) δ 7.26 (s, 1H), 3.33 (s, 2H), 3.29-3.20 (m, 2H),1.85-1.75 (m, 4H), 1.70-1.60 (m, 1H), 1.55-1.40 (m, 4H), 1.30-1.20 (m,3H), 1.18-1.05 (m, 3H), 0.93 (d, 6H), 0.89 (t, 3H)

HPLC-MS: m/z=415, R_(t)=2.4 min

Example 22{2-[3-(4-trans-Ethyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid, from 4-trans-ethyl-cyclohexylamine hydrochloride, 2-phenethylbromide and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, CDCl₃) δ 7.32-7.20 (m, 6H), 3.51 (m, 2H), 3.32 (s, 2H),2.90 (m, 2H), 1.83 (m, 4H), 1.57-1.49 (m, 2H), 1.25 (m, 3H), 1.12 (m,3H), 0.89 (t, 3H

HPLC-MS: m/z=448, R_(t)=2.4 min

Example 23{2-[3-(2-Cyclohexyl-ethyl)-3-(4-trans-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid, from 4-trans-ethyl-cyclohexylamine hydrochloride,2-cyclohexylethyl bromide and (2-amino-thiazol-5-ylsulfanyl)-acetic acidethyl ester.

¹H NMR (400 MHz, CDCl₃) δ 7.26 (s, 1H), 3.32 (s, 2H), 3.28 (m, 2H),1.84-1.64 (m, 10H), 1.47 (m, 4H), 1.34 (m, 1H), 1.25-1.10 (m, 9H), 0.95(m, 2H), 0.89 (t, 3H);

HPLC-MS: m/z=455, R_(t)=2.7 min

Example 243-{2-[3-(4-trans-Ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of{2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid, from 4-trans-ethyl-cyclohexylamine hydrochloride,1-bromo-3-methylbutane and (2-amino-thiazol-5-ylsulfanyl)-propionic acidethyl ester.

¹H NMR (400 MHz, CDCl₃) δ 7.25 (s, 1H), 3.22 (m, 2H), 2.99 (m, 2H), 2.73(m, 2H), 1.86 (m, 4H), 1.61 (m, 2H), 1.45 (m, 4H), 1.25 (m, 4H), 1.12(m, 2H), 0.97-0.89 (m, 9H).

HPLC-MS: m/z=429, R_(t)=2.5 min

Example 253-{2-[3-(4-trans-Ethyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of{2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid, from 4-trans-ethyl-cyclohexylamine hydrochloride, 2-phenethylbromide and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

¹H NMR (400 MHz, CDCl₃) δ 7.27-7.18 (m, 6H), 3.43 (broad s, 2H), 2.87(m, 4H), 2.72 (m, 2H), 1.89 (m, 4H), 1.52-1.43 (m, 2H), 1.26-1.09 (m,5H), 0.88 (m, 3H).

HPLC-MS: m/z=463, R_(t)=2.5 min

Example 263-{2-[3-(2-Cyclohexyl-ethyl)-3-(4-trans-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of{2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid, from 4-trans-ethyl-cyclohexylamine hydrochloride,2-cyclohexylethyl bromide and (2-amino-thiazol-5-ylsulfanyl)-propionicacid ethyl ester.

¹H NMR (400 MHz, CDCl₃) δ 7.25 (s, 1H), 3.23 (m, 2H), 2.98 (m, 2H), 2.73(m, 2H), 1.86 (m, 4H), 1.74-1.64 (m, 6H), 1.50-1.42 (m, 4H), 1.28-1.10(m, 10H), 0.98-0.86 (m, 6H)

HPLC-MS: m/z=469, R_(t)=2.8 min

Example 272-{2-[3-(4-trans-Ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionicacid

Preparation of 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acidethyl ester

2-Aminothiazole (35 g, 350 mmol) and sodium thiocyanate (89 g, 1.08 mol)in MeOH (400 mL) was stirred at −10° C. Bromine (18.0 mL, 350 mmol)dissolved in MeOH (100 mL) saturated with NaBr was slowly added keepingthe internal temperature between −10 and 0° C. After the addition themixture was stirred at 0° C. for 3 h and the reaction mixture was pouredinto ice water (1500 mL). Aqueous NH₄OH was added to pH ca 8.5 causingprecipitation of light yellow crystals which were isolated byfiltration, washed with ice water and dried in a vacuum oven to give 30g (55%) 5-thiocyanato-thiazol-2-ylamine as light yellow crystals.

Step 2:

In a nitrogen atmosphere 5-thiocyanato-thiazol-2-ylamine (10 g, 64 mmol)dissolved in MeOH (300 mL) was added 2,3-dihydroxy-1,4-dithiolbutane(DTT, 9.8 g, 64 mmol) and stirred at room temperature for 1½ h. Then2-bromo-2-methyl-propionic acid ethyl ester (13.6 g, 70 mmol) and K₂CO₃(10.5 g, 76 mmol) was added and the reaction mixture was stirred forfurther 16 h. Addition of water (500 mL) and EtOAc (500 mL). Separationof the organic phase followed by extraction of the aqueous phase withEtOAc (2×300 mL). The combined organic phases were washed with water(500 mL) and brine (2×400 mL) and dried (MgSO₄), filtered andevaporated.¹ The crude product was dissolved in a small amount of DCMand purified by flash chromathography (heptane/EtOAc 2:1->1:2).Fractions containing the product were pooled and evaporated to a product(ca 14 g) containing impurities of DDT. The crude product was dissolvedin diethyl ether (100 mL) and washed with water eight times. The etherphase was dried (MgSO₄), filtered and evaporated to give 8.45 g (54%) of95% pure 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethylester as light brown crystals. ¹As the DTT impurities is not easilyremoved by flash chromathography it's recommended that the crude productis dissolved in Et2O and subsequently washed with water several times atthen purified by flash chromathography.

2-{2-[3-(4-trans-Ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionicacid was prepared as described for the synthesis of{2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid, from 4-trans-ethyl-cyclohexylamine hydrochloride,1-bromo-3-methylbutane and2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.

¹H NMR (400 MHz, CDCl₃) δ 7.05 (s, 1H), 3.31 (m, 2H), 1.85 (m, 4H), 1.67(m, 2H), 1.59 (s, 6H), 1.51 (m, 4H), 1.23 (m, 3H), 1.12 (m, 3H), 0.94(d, 6H), 0.89 (t, 3H)

HPLC-MS: m/z=442, R_(t)=2.5 min

Example 282-{2-[3-(4-trans-Ethyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionicacid

Prepared as described for the synthesis of{2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid, from 4-trans-ethyl-cyclohexylamine hydrochloride, 2-phenethylbromide and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acidethyl ester.

¹H NMR (400 MHz, CDCl₃) δ 7.31-7.21 (m, 5H), 7.07 (s, 1H), 3.54 (bs,2H), 2.94 (m, 2H), 1.87 (m, 4H), 1.59 (s, 6H), 1.54 (m, 2H), 1.25-1.20(m, 4H), 1.13 (broad m, 2H), 0.89 (t, 3H)

HPLC-MS: m/z=477, R_(t)=2.6 min

Example 29{2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylamino}-aceticacid

(General Procedure (H) (B) and (A Step 2))

Preparation of 2-Amino-thiazole-5-sulfonic acid amides

Step 1. A mixture of glycine ethylester hydrochloride (15 mmol),2-acetylamino-thiazole-5-sulfonyl chloride (12 mmol) (prepared asdescribed in J. Am. Chem. Soc 69, 2063, 1947), DIPEA (35 mmol) in DCM(50 mL) was stirred at room temperature over night. Addition of waterand 1N HCl to pH 2 resulted in precipitation. The precipitate wasisolated by filtration, washed with water and dried to give(2-acetylamino-thiazole-5-sulfonylamino)-acetic acid ethyl ester (64%)as crystals. This was suspended in EtOH (15 mL) and added 4N HCl indioxane (15 mL) and heated for 4 h at 80° C. and then cooled to roomtemperature. Addition of aqueous NaHCO3 to neutral pH. The organic phasewas isolated and the aqueous phase was extracted with CH₂Cl₂, and thecombined organic phases were dried and concentrated in vacuo to give(2-amino-thiazole-5-sulfonylamino)-acetic acid ethyl ester (80%) ascolourless crystals.

Coupling:

An equimolar mixture of 1,1-carbonyldiimidazole,(2-amino-thiazole-5-sulfonylamino)-acetic acid ethyl ester and DMAP (5mol %) in THF was heated for 5 h at 50-60° C. and then cooled to roomtemperature. Then (3-methyl-butyl)-(4-methyl-cyclohexyl)-amine (1equivalent; pre-pared following the procedure described in thepreparation of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid)was added and the reaction is stirred overnight at room temperature. Thereaction mixture was quenched with water. The organic phase was isolatedand the aqueous phase was extracted with CH₂Cl₂, and the combinedorganic phases were dried and concentrated in vacuo. The crude productwas dissolved in MeCN and purified using HPLC to give{2-[3-(3-methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylamino}-aceticacid ethyl ester as crystals.

Hydrolysis:

{2-[3-(3-methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylamino}-aceticacid ethyl ester was dissolved in MeOH and treated with 15 equivalentsof 1N NaOH for 2 days at room temperature. MeOH was removed byevaporation. Addition of 1N HCl to pH<1 caused precipitation. Theprecipitate was isolated by filtration, washed with water and dried togive{2-[3-(3-methyl-butyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylamino}-aceticacid as crystals.

¹H NMR (400 MHz, CDCl₃+2 dr DMSO) δ 7.80 (s, 1H), 6.68 (br t, 1H), 4.00(br s, 1H), 3.74 (d, 2H), 3.29-3.23 (m, 2H), 1.80-1.08 (m, 12H), 0.95(d, 6H), 0.91 (d, 3H).

HPLC-MS: m/z=447, R_(t)=2.13 min

Example 303-{2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylamino}-propionicacid

Prepared as described for the preparation of{2-[3-(3-methyl-butyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylamino}-aceticacid using the appropriate amino ester in Step 1.

¹H NMR (400 MHz, CDCl₃+2dr DMSO) δ 7.80 (s, 1H), 6.38 (br t, 1H), 3.99(br s, 1H), 3.28-3.21 (m, 4H), 2.55 (t, 2H), 1.80-1.07 (m, 12H), 0.97(d, 6H), 0.92 (d, 3H).

HPLC-MS: m/z=461, R_(t)=2.13 min

Example 31(Methyl-{2-[3-(3-methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-amino)-aceticacid

Prepared as described for the preparation of{2-[3-(3-methyl-butyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylamino}-aceticacid using the appropriate amino ester in Step 1.

¹H NMR (400 MHz, DMSO) δ 7.89 (s, 1H), 3.97 (br t, 1H), 3.88 (s, 2H),3.26 (br t, 2H), 2.82 (s, 3H), 1.73-1.01 (m, 12H), 0.90 (d, 6H), 0.88(d, 3H).

HPLC-MS: m/z=461, R_(t)=2.24 min

Example 32(S)-1-{2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-pyrrolidine-2-carboxylicacid

Prepared as described for the preparation of{2-[3-(3-methyl-butyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylamino}-aceticacid using the appropriate amino ester in Step 1.

¹H NMR (400 MHz, DMSO) δ 12.75 (br s, 1H), 11.4 (br s, 1H), 7.93 (s,1H), 4.02 (dd, 1H), 3.97 (brt, 1H), 3.45-3.39 (m, 1H), 3.27-3.18 (m,3H), 2.05-1.02 (m, 16H), 0.90 (d, 6H), 0.88 (d, 3H).

HPLC-MS: m/z=487, R_(t)=2.27 min

Example 33{2-[3-(4-trans-tert-Butyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid, from 4-trans-tert-butyl-cyclohexylamine hydrochloride,1-bromo-3-methylbutane and (2-amino-thiazol-5-ylsulfanyl)-acetic acidethyl ester

1H NMR (400 MHz, CDCl₃) δ 7.26 (s, 1H), 3.95 (bs, 1H), 3.32 (s 2H), 3.27(m, 2H), 1.84 (m, 4H), 1.65 (m, 1H), 1.48 (m, 4H), 1.25 (m, 2H), 0.98(m, 1H), 0.94 (d, 6H), 0.87 (s, 9H).

HPLC-MS: m/z=442, R_(t)=2.5 min

Example 34{2-[3-(4-trans-Isopropyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid, from 4-trans-isopropyl-cyclohexylamine hydrochloride,1-bromo-3-methylbutane and (2-amino-thiazol-5-ylsulfanyl)-acetic acidethyl ester

¹H NMR (400 MHz, CDCl₃) δ 7.22 (s, 1H), 4.02 (broad s, 1H), 3.31 (s 2H),3.27 (m, 2H), 1.81 (m, 4H), 1.66 (m, 1H), 1.53-1.43 (m, 5H), 1.23 (m,2H), 1.05 (m, 1H), 0.94 (d, 6H), 0.88 (d, 6H).

HPLC-MS: m/z=428, R_(t)=2.5 min

Example 353-{2-[3-(4-trans-tert-Butyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of{2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid, from 4-trans-tert-butyl-cyclohexylamine hydrochloride,1-bromo-3-methylbutane and (2-amino-thiazol-5-ylsulfanyl)-propionic acidethyl ester

¹H NMR (400 MHz, CDCl₃) δ 7.25 (s, 1H), 3.65 (broad s, 1H), 3.21 (m,2H), 2.99 (broad m, 2H), 2.72 (m, 2H), 1.88 (m, 4H), 1.62 (m, 1H), 1.44(m, 3H), 1.31 (m, 1H), 0.98 (m, 2H), 0.93 (d, 6H), 0.89 (s, 9H)

HPLC-MS: m/z=456, R_(t)=2.6 min

Example 363-{2-[3-(4-trans-Isopropyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of{2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid, from 4-trans-isopropyl-cyclohexylamine hydrochloride,1-bromo-3-methylbutane and (2-amino-thiazol-5-ylsulfanyl)-propionic acidethyl ester.

¹H NMR (400 MHz, CDCl₃) δ 7.25 (s, 1H), 3.65 (broad s, 1H), 3.21 (m,2H), 2.99 (broad m, 2H), 2.73 (m, 2H), 1.90 (m, 2H), 1.82 (m, 3H), 1.61(m, 2H), 1.45 (m, 4H), 1.27 (m, 1H), 1.04 (m, 1H), 0.93 (d, 6H), 0.89(s, 9H).

HPLC-MS: m/z=442, R_(t)=2.5 min

Example 37{2-[3-(4-Methyl-cyclohexyl)-3-(3-phenyl-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidusing 3-phenylpropionaldehyde, trans-4-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.41 (s, 1H), 7.32-7.25 (m, 5H), 4.10-3.9(m, 1H), 3.48 (s, 2H), 3.3-3.2 (m, 2H), 2.59 (t, 2H), 1.95-0.95 (m,11H), 0.87 (d, 3H)

HPLC-MS: m/z=448 (M+1)

Example 38{2-[3-(3-Methyl-butyl)-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

(General Procedure (E), (A) and (B))

General Synthesis of trans-4-alkoxy-cyclohexylamine Intermediates

Trans 4-aminocyclohexanol (25 g, 0.22 mol) dissolved in water (350 mL)was added potassium carbonate (3.0 g, 0.022 mol) andN-carbethoxyphthalimide (47.6 g, 0.22 mol) and the reaction mixture wasstirred for 16 hours. The white precipitate was filtered off, washedwith water and dried to give 37.7 g (71%) oftrans-2-(4-hydroxycyclohexyl)-isoindole-1,3-dione (J. Med. Chem. 1996,39, 314-322).

To a solution of trans-2-(4-hydroxycyclohexyl)-isoindole-1,3-dione (13g, 53 mmol) in dry DMF (50 mL) was added molecular sieves (4 Å, 6 mL).The mixture was stirred for 30 min at rt. NaH (5.3 g 60% in oil, 132.5mmol) was washed with hexanes before it was added in portions to thereaction mixture. The mixture was stirred for 30 min beforepropylbromide (48.1 mL, 530 mmol) was added. The reaction mixture wasstirred for 16 hours before the reaction mixture was filtered. Thefiltrate was added water (100 mL) and extracted with Et₂O (250 mL). Theorganic phase was washed with brine (3×50 mL) and dried (MgSO₄) and thesolvent was removed in vacuo. The crude product was purified by columnchromatography (silica gel, heptane-EtOAc (4:1). The first band wascollected to give 6.6 g (43%) oftrans-2-(4-propyloxycyclohexyl)-isoindole-1,3-dione.

¹H-NMR (CDCl₃): 7.8 (s, 2H), 7.7 (s, 2H), 4.15 (m, 1H), 3.45 (t, 2H),3.35 (m, 1H), 2.3 (m, 2H), 2.15 (m, 2H), 1.8 (m, 2H), 1.6 (h, 2H), 1.37(m, 2H), 0.92 (t, 3H)

Hydrazine hydrate (1.76 g, 55 mmol) was added to a solution oftrans-2-(4-propyloxycyclohexyl)-isoindole-1,3-dione (7.90 g, 27.5 mmol)in absolute EtOH (100 mL). The reaction was stirred at 50° C. for 3 hbefore the reaction mixture was filtered. The solvent was removed invacuo and Et₂O (250 mL) was added after stirring for 30 min the solidwas filtered off and the filtrate was added 150 mL 1 N HCl, the phaseswere separated and the aqueous phase was washed with Et₂O (150 mL)before 10 N NaOH was added (until pH=11-12). The aqueous phase wasextracted with EtOAc (200 mL+2×100 mL) and the organic fractions werecollected and dried (MgSO₄) to give 3.11 g (72%) oftrans-4-propoxy-cyclohexylamine.

¹H-NMR (CDCl₃): 3.4 (t, 2H), 3.18 (m, 1H), 2.7 (m, 1H), 2.0 (m, 2H),1.85 (m, 2H), 1.55 (h, 2H), 1.4-1.1 (m, 4H), 0.9 (t, 3H).

(Reductive Amination, Coupling and Hydrolysis):

{2-[3-(3-Methyl-butyl)-3-(4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid was prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidusing isovaleraldehyde, trans-4-propoxy-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 4.1-3.9 (m, 1H), 3.48 (s, 2H),3.25-3.15 (m, 3H), 2.05-1.95 (m, 2H), 1.7-1.2 (m, 13H), 0.90 (d, 6H),0.87 (t, 3H).

HPLC-MS: m/z=444 (M+1)

Example 39{2-[3-(trans-4-tert-Butoxy-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidusing isovaleraldehyde, trans-4-tert-butoxy-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 4.00-3.38 (m, 1H), 3.48 (s,2H), 3.5-3.3 (m, 1H), 3.25-3.15 (m, 2H), 1.8-1.2 (m, 11H), 1.15 (s, 9H),0.90 (d, 6H).

HPLC-MS: m/z=458 (M+1)

Example 40{2-[3-(trans-4-Cyclopropylmethoxy-cyclohexyl)-3-(3-methyl-butyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidusing isovaleraldehyde, trans-4-cyclopropylmethoxy-cyclohexylamine(prepared in accordance with the general method given for thepreparation of{2-[3-(3-methyl-butyl)-3-(4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid) and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 4.05-1.90 (m, 1H), 3.48 (s,1H), 3.23 (d, 2H), 3.25-3.15 (m, 3H), 2.05-1.95 (m, 2H), 1.70-1.15 (m,9H), 1.0-0.9 (m, 1H), 0.90 (d, 6H), 0.48-0.40 (m, 2H), 0.18-0.10 (m,2H).

HPLC-MS: m/z=456 (M+1)

Example 41{2-[3-[trans-4-(2-Methoxy-ethoxy)-cyclohexyl]-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidusing isovaleraldehyde, trans-4-(2-methoxy-ethoxy)-cyclohexylamine(prepared in accordance with the general method given for thepreparation of{2-[3-(3-methylbutyl)-3-(4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid) and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 4.05-3.85 (m, 1H), 3.05-3.38(m, 4H), 3.49 (s, 2H), 3.25 (s, 3H), 3.28-3.15 (m, 3H), 2.05-1.95 (m,2H), 1.65-1.15 (m, 10H), 0.90 (d, 6H).

HPLC-MS: m/z=460 (M+1)

Example 42{2-[3-(trans-4-Benzyloxy-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidusing isovaleraldehyde, trans-4-benzyloxy-cyclohexylamine (prepared inaccordance with the general method given for the preparation of{2-[3-(3-methyl-butyl)-3-(4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid) and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.41 (s, 1H), 7.38-7.23 (m, 5H), 4.50 (s,2H); 4.05-3.95 (m, 1H); 3.48 (s, 2H), 3.40-3.25 (s, 1H), 3.25-3.15 (m,2H); 2.12-2.02 (m, 2H), 1.70-1.28 (m, 9H), 0.88 (d, 6H).

HPLC-MS: m/z=492 (M+1)

Example 43{2-[3-(trans-4-Methoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

(General Procedure (D), (A) and (B))

Preparation of trans-4-alkoxymethyl-cyclohexyl amine

A mixture of 4-carboxymethylcyclohexanone (21 g), ethylene glycol (19 g)and benzene (250 mL) was heated at reflux for 20 h with Dean Starkazeotropic removal of water. After cooling the solution was washed withsodium bicarbonate solution, dried over magnesium sulphate andconcentrated. The crude ketal was then taken up in diethyl ether (250mL) and lithium aluminium hydride (7 g) was added. The mixture wasstirred overnight and then water (20 mL), 10% sodium hydroxide (30 mL)and water (30 mL) was added carefully. Sodium sulphate (30 g) was thenadded and the mixture stirred for 20 min. The insoluble material wasremoved by filtration and the organic phase concentrated in vacuo togive (1,4-dioxaspiro[4.5]dec-8-yl)-methanol (21 g).

¹H NMR (400 MHz, CDCl₃) δ 1.20-1.80, (m, 10H), 3.45 (d, 2H), 3.95 (s,4H)

To (1,4-dioxa-spiro[4.5]dec-8-yl)-methanol (10 g) in tetrahydrofuran(300 mL) in an ice bath was added sodium hydride (3.6 g of 60% inmineral oil) and the mixture stirred for 30 min. Methyl iodide 7.8 mL inTHF (20 mL) was added dropwise and the reaction was allowed to warmslowly to room temperature overnight. Water (20 mL) was added and thereaction mixture partially concentrated, then partitioned between water(100 mL) and diethyl ether (300 mL). The organic phase was isolated,dried and concentrated in vacuo. The crude was then taken up intetrahydrofuran (250 mL) and 40 mL of 3N aqueous HCl was added. Thereaction was stirred for 2 h at room temperature, partially concentratedand then the crude product was extracted with diethyl ether, dried,concentrated and purified by flash chromatography (4 hexane: 1 ethylacetate) to give 4-methoxymethyl-cyclohexanone 4.9 g.

¹H NMR (400 MHz, CDCl₃) δ 1.40-1.55 (m, 2H), 1.98-2.15 (m, 3H),2.20-2.45 (m, 4H), (d, 2H), 3.36 (d, 4H), 3.31 (s. 3H).

A mixture of 4-methoxymethyl-cyclohexanone (5 g), hydroxylaminehydrochloride (4.7 g), and sodium acetate (5.6 g) in water (125 mL) andmethanol (25 mL) was heated to 60° C. for 18 h. ether was added and theorganic phase isolated, washed with saturated sodium bicarbonate, driedover magnesium sulphate and concentrated in vacuo. Ethanol was added andthen sodium (8 g) was added portion wise. The mixture was then heated to65° C. for 1.5 h, cooled in an ice bath and water (10 mL) was carefullyadded. The reaction was partially concentrated, water (30 mL) was addedand the aqueous phase was extracted with diethyl ether and concentratedto give the crude product. Addition of 6N HCl afforded the correspondingHCl salt which was recrystallised from acetonitrile to givetrans-4-methoxymethyl-cyclohexylamine hydrochloride (3 g).

¹H NMR (400 MHz, DMSO-d₆) δ 0.90-1.15 (m, 2H), 1.20-1.37 (m, 2H),1.38-1.54 (m, 1H), 1.73 (d, 2H), 1.95 (d, 2H), 2.80-2.95 (m, 1H), 3.12(d, 2H), 3.22 (s. 3H), 8.21 (s, 3H).

(Reductive Amination, Coupling and Hydrolysis):

{2-[3-(trans-4-Methoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid was prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidusing, trans-4-methoxymethyl-cyclohexylamine, isovaleraldehyde and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 4.02-3.95 (m, 1H), 3.48 (s,2H), 3.28-3.17 (m, 2H), 3.23 (s, 3H), 3.13 (d, 2H), 1.80-1.30 (m, 10H),1.15-0.98 (m, 2H), 0.90 (d, 6H).

HPLC-MS: m/z=430 (M+1)

Example 44{2-[3-(trans-4-Ethoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidusing isovaleraldehyde, trans-4-ethoxymethyl-cyclohexylamine (preparedin accordance with the general method given for the preparation of{2-[3-(4-methoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid) and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 4.10-3.90 (m, 1H), 3.48 (s,2H), 3.38 (q, 2H), 3.26-3.15 (m, 2H), 3.18 (d, 2H), 1.80-1.70 (m, 2H),1.70-1.30 (m, 9H), 1.10 (t, 3H), 0.90 (d, 6H)

HPLC-MS: m/z=444 (M+1)

Example 45{2-[3-(trans-4-Cyclopropylmethoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidusing isovaleraldehyde,trans-4-cyclopropyl-methoxymethyl-cyclohexylamine (prepared inaccordance with the general method given for the preparation of{2-[3-(4-methoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid) and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 4.05-3.90 (m, 1H), 3.48 (s,2H), 3.25-3.50 (m, 6H) 1.85-0.95 (m, 13H), 0.90 (d, 6H), 0.50-0.40 (m,2H), 0.20-0.10 (m, 2H)

HPLC-MS: m/z=470 (M+1)

Example 46{2-[3-Butyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidusing butyraldehyde, trans-4-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 4.00-3.88 (m, 1H), 3.48 (s,2H), 3.25-3.15 (m, 2H), 1.75-0.95 (m, 13H), 0.93-0.81 (m, 6H)

HPLC-MS: m/z=386 (M+1)

Example 47{2-[3,3-Bis-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidusing isovaleraldehyde, 3-methylbutylamine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 3.49 (s, 2H), 3.40-3.20 (m,4H), 1.60-1.49 (m, 2H), 1.42-1.33 (m, 4H), 0.90 (d, 12H).

HPLC-MS: m/z=374 (M+1)

Example 48{2-[3-Butyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidusing isovaleraldehyde, butylamine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.41 (s, 1H), 3.48 (s, 2H); 3.35-3.2 (m,4H), 1.60-1.20 (m, 7H), 0.92-0.82 (m, 9H).

HPLC-MS: m/z=360 (M+1)

Example 493-{2-[3,3-Bis-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidusing isovaleraldehyde, 3-methyl-butylamine and(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.39 (s, 1H), 3.40-3.28 (m, 4H), 2.84 (t,2H), 2.50 (t, 2H), 1.61-1.49 (m, 2H), 1.42-1.32 (m, 4H), 0.89 (d, 6H).

HPLC-MS: m/z=388 (M+1)

Example 502-[3-(4-trans-Ethyl-cyclohexyl)-3-(2-phenoxy-ethyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid, from 4-trans-ethyl-cyclohexylamine hydrochloride,2-bromoethoxybenzene and (2-amino-thiazol-5-ylsulfanyl)-acetic acidethyl ester.

¹H NMR (400 MHz, CDCl₃) δ 7.30-7.25 (m. 3H), 6.97-6.88 (m, 3H), 4.11 (m,3H), 3.71 (m, 2H), 3.27 (s, 2H), 1.84 (m, 4H), 1.56 (m, 2H), 1.25-1.10(m, 7H), 0.88 (m, 4H).

HPLC-MS: m/z=464 (M+1)

Example 51{2-[3-(4-trans-Ethyl-cyclohexyl)-3-(4-phenoxy-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid, from 4-trans-ethyl-cyclohexylamine hydrochloride,4-bromobutoxybenzene and (2-amino-thiazol-5-ylsulfanyl)-acetic acidethyl ester.

¹H NMR (400 MHz, CDCl₃) δ 7.30-7.23 (m, 3H), 6.95-6.85 (m, 3H), 3.99 (m,3H), 3.33 (m, 2H), 3.30 (s, 2H), 1.87-1.75 (m, 8H), 1.50 (m, 2H), 1.23(m, 2H), 1.08 (m, 2H), 0.88 (t, 3H).

HPLC-MS: m/z=514 (M+1)

Example 523-{2-[3-Butyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidusing isovaleraldehyde, butylamine and(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) 7.39 (s, 1H), 3.80-3.25 (m, 4H), 2.84 (t, 2H),2.50 (t, 2H), 1.60-1.20 (7H), 0.95-0.84 (m, 9H).

HPLC-MS: m/z=374 (M+1)

Example 532-Methyl-2-{2-[3-(3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from 4-trans-methyl-cyclohexylamine, isovaleraldehyde and2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 3.97 (m, 1H), 3.21 (m, 2H),1.75-1.25 (m, 10H), 1.39 (s, 6H), 1.15-1.00 (m, 2H), 0.90 (d, 6H), 0.87(d, 3H)

HPLC-MS: m/z=428

Example 542-{2-[3-Cyclohexyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionicacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from cyclohexanone, 3-methylbutylamine and2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 3.97 (m, 1H), 3.23 (m, 2H),1.80-1.00 (m, 13H), 1.40 (s, 6H)

HPLC-MS: m/z=415

Example 555-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazole-2-carboxylicacid ethyl ester

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from 4-trans-methyl-cyclohexylamine, isovaleraldehyde and5-amino-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester.

HPLC-MS: m/z=383

Example 56{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-ylsulfanyl}-aceticacid ethyl ester

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from 4-trans-methyl-cyclohexylamine, isovaleraldehyde and(5-amino-[1,3,4]thiadiazol-2-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=429

Example 572-Methyl-2-{5-[3-(3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from 4-trans-methyl-cyclohexylamine, isovaleraldehyde and(2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.

HPLC-MS: m/z=429

Example 58{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-ylsulfanyl}-aceticacid

Prepared by hydrolysis of{5-[3-(3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-ylsulfanyl}-aceticacid ethyl ester described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid.

HPLC-MS: m/z=401

Example 593-{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-ylsulfanyl}-propionicacid ethyl ester

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from 4-trans-methyl-cyclohexylamine, isovaleraldehyde and3-(5-amino-[1,3,4]thiadiazol-2-ylsulfanyl)-propionic acid ethyl ester

HPLC-MS: m/z=443

Example 603-{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-yl}-propionicacid methyl ester

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid,from 4-trans-methyl-cyclohexylamine, isovaleraldehyde and3-(5-amino-[1,3,4]thiadiazol-2-yl)-propionic acid methyl ester

HPLC-MS: m/z=397

Example 61{2-[3-(1,3-Dimethyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidfrom (1,3-dimethyl-butyl)-(4-trans-methyl-cyclohexyl)-amine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester

¹H NMR (400 MHz, DMSO-d₆) δ 7.38 (s, 1H), 3.68-3.55 (m, 1H), 3.50-3.20(m, 1H), 3.48 (s, 2H), 1.80-0.95 (m, 15H), 0.92-0.80 (m, 9H)

HPLC-MS: m/z=415

Preparation of (1,3-dimethyl-butyl)-(4-trans-methyl-cyclohexyl)-amine

4-trans-methyl-cyclohexylamine hydrochloride (3.74, 24.96 mmol) inanhydrous MeOH (40 mL) was added NaOH (1.0 g, 24.96 mmol) followed byisobutylmethylketone (2.5 g, 24.96 mmol) and the reaction mixture wasstirred for 30 min before glacial acetic acid (15 mL), and Pd/C (10%,375 mg) was added. The reaction mixture was stirred at room temperatureunder H₂ (1 atm) for 18 hours before more isobutylmethylketone (1.25 g,12.48 mmol) was added. The reaction was then left stirring under H₂ for72 hours before it was filtered through a pad of celite. The filtratewas concentrated in vacuo, dissolved in diethyl ether and washed twicewith saturated sodium bicarbonate (50 mL). The organic phase wasacidified by adding 1N HCl in diethyl ether (25 mL). The precipitatedproduct was collected by filtration to give 2.9 g of(1,3-dimethyl-butyl)-(4-trans-methyl-cyclohexyl)-amine.

Example 622-{2-[3-(1,3-Dimethyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionicacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidfrom (1,3-dimethyl-butyl)-(4-trans-methyl-cyclohexyl)-amine and(2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester

¹H NMR (400 MHz, DMSO-d₆) δ 7.35 (s, 1H), 3.60-3.10 (m, 2H), 1.72-0.95(m, 15H), 1.38 (s, 6H), 0.92-0.82 (m, 9H)

HPLC-MS: m/z=443

Example 633-{2-[3-(1,3-Dimethyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidfrom (1,3-dimethyl-butyl)-(4-trans-methyl-cyclohexyl)-amine and(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.35 (s, 1H), 2.83 (t, 2H), 2.49 (t, 2H),1.75-0.95 (m, 15H), 0.91-0.82 (m, 9H)

HPLC-MS: m/z=429

Example 643-{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-ylsulfanyl}-propionicacid

Prepared by hydrolysis of3-{5-[3-(3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-ylsulfanyl}-propionicacid ethyl ester as described for the preparation of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid

HPLC-MS: m/z=415

Example 653-{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-yl}-propionicacid

Prepared by hydrolysis of3-{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-yl}-propionicacid methyl ester as described for the preparation of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid

HPLC-MS: m/z=383

Example 66{2-[3-(2-Benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

To a solution of 2-benzyloxyethanol (305 mg, 2.0 mmol) and DIPEA (0.69mL, 4.0 mmol) in DCM (5 mL) cooled on an ice bath was addedmesylchloride (0.19 mL, 2.5 mmol). The reaction mixture was stirred for15 min before the ice bath was removed. After stirring for an additional45 min the reaction mixture was washed with aqueous HCl (0.1 N, 5 mL).The aqueous phase was extracted with dichloromethane (2×5 mL) and thecombined organic phases were dried (MgSO₄), filtered and concentrated invacuo.

The residue was dissolved in acetonitrile (5 mL) before DIPEA (0.34 mL,2.0 mmol) and 4-trans-methyl-cyclohexylamine (226 mg, 2.0 mmol) wereadded. The reaction mixture was refluxed for 18 hours before thevolatiles were removed in vacuo.

The residue was dissolved in tetrahydrofuran (2 mL) and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester (655 mg, 3.0mmol), carbonyl diimidazole (487 mg, 3.0 mmol) and4-(dimethylamino)pyridine (12 mg, 0.1 mmol) were added. The reactionmixture was stirred for 2 hours before the volatiles were removed invacuo.

The residue was dissolved in methanol (2.5 mL) and NaOH (2N, 5 mL, 10mmol) was added. The mixture was stirred for 2 hours before HCl (1 mL,conc.) was added. The solvent was removed in vacuo beforetetrahydrofuran, 5 mL) was added and the mixture was filtered. Thefiltrate was purified on a preparative HPLC to give 230 mg{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.41 (s, 1H), 7.35-7.23 (m, 5H), 4.53 (s,2H), 3.92 (m, 1H), 3.57-3.44 (m, 6H), 1.73-1.45 (m, 6H), 1.35-1.25 (m,1H), 1.10-0.95 (m, 1H), 0.86 (d, 3H)

HPLC-MS: m/z=465

Example 67{2-[3-(2-isopropoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-isopropoxyethanol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 4.0-3.84 (m, 1H), 3.70-3.20(m, 7H), 1.80-0.93 (m, 18H) (with the following distinct signal: 1.12(d, 6H)), 0.86 (d, 3H)

HPLC-MS: m/z=417

Example 68{2-[3-(2-tert-Butoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-tert-butoxyethanol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.41 (s, 1H), 3.92 (t, 1H), 3.53-3.33 (m,6H), 1.75-1.25 (m, 7H), 1.19 (s, 9H), 1.10-0.95 (m, 2H), 0.87 (d, 3H)

HPLC-MS: m/z=431

Example 69{2-[3-(2-Cyclohexyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-cyclohexyloxyethanol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=457

Example 70(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-ethanol,4-trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-aceticacid ethyl ester.

HPLC-MS: m/z=525

Example 71{2-[3-(2-Ethoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-ethoxyethanol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=403

Example 72{2-[3-(2-Iso-butoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-isobutoxyethanol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=431

Example 73(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2,2,2-trifluoro-ethoxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(2,2,2-trifluoroethoxyethanol,4-trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-aceticacid ethyl ester.

HPLC-MS: m/z=457

Example 74{2-[3-(3-Methoxy-3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 3-methoxy-3-methylbutan-1-ol, 4-trans-methyl-cyclohexylamineand (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.41 (s, 1H), 4.04-3.91 (m, 1H), 3.47 (s,2H), 3.47-3.27 (m, 4H), 3.26-3.16 (m, 3H), 1.75-0.95 (m, 15H), (withfollowing distinct signal: 1.13 (s, 6H)), 0.87 (d, 3H)

HPLC-MS: m/z=431

Example 753-{2-[3-(2-Benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-benzyloxyethanol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester

HPLC-MS: m/z=479

Example 763-{2-[3-(2-Iso-propoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-iso-propoxyethanol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

HPLC-MS: m/z=431

Example 773-{2-[3-(2-tert-Butoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-tert-butoxyethanol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

HPLC-MS: m/z=445

Example 783-{2-[3-(2-Cyclohexyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-cyclohexyloxyethanol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

HPLC-MS: m/z=471

Example 793-(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-propionicacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(2,2,2-Trifluoro-1-trifluoromethyl-ethoxy)-ethanol,4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

HPLC-MS: m/z=539

Example 803-{2-[3-(2-Iso-butoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-isobutoxyethanol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

HPLC-MS: m/z=444

Example 813-(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2,2,2-trifluoro-ethoxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-propionicacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(2,2,2-trifluoroethoxyethanol,4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

HPLC-MS: m/z=471

Example 823-{2-[3-(3-Methoxy-3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 3-methoxy-3-methylbutan-1-ol, 4-trans-methyl-cyclohexylamineand (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

HPLC-MS: m/z=445

Example 83{2-[3-(4-trans-methyl-cyclohexyl)-3-(2-phenoxy-ethyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-phenoxyethanol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=451

Example 84{2-[3-(3-Ethoxy-propyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 3-ethoxypropanol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=417

Example 85{2-[3-(3-Methoxy-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 3-methoxy-butan-1-ol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=417

Example 86{2-[3-(3-Benzyloxy-propyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 3-benzyloxypropanol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=479

Example 873-{2-[3-(4-trans-methyl-cyclohexyl)-3-(2-phenoxy-ethyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-phenoxyethanol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

HPLC-MS: m/z=465

Example 883-{2-[3-(3-Ethoxy-propyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-ethoxypropanol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

HPLC-MS: m/z=431

Example 89{2-[3-(2-Benzyloxy-1-methyl-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Benzyloxyacetone (0.50 g, 3.0 mmol) and 4-trans-methyl-cyclohexylamine(0.313 g, 2.79 mmol) in THF-MeOH (50 mL, 2:1) and AcOH (5 mL) was addedsodium cyanoborohydride (0.26 g, 4.15 mmol) in small portions over 15min. The reaction mixture was stirred for 16 hours before the solventwas removed in vacuo. The residue was divided between Et₂O (150 mL) andaqueous NaOH (10 M, 50 mL). The aqueous phase was extracted twice withEt₂O (100 mL), and the combined organic extracts were dried (MgSO₄),filtered and dried in vacuo to give(2-benzyloxy-1-methyl-ethyl)-(4-trans-methyl-cyclohexyl)-amine.

{2-[3-(2-Benzyloxy-1-methyl-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid was then prepared using the procedure described for the synthesisof [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-aceticacid from (2-benzyloxy-1-methyl-ethyl)-(4-trans-methyl-cyclohexyl)-amineand (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 7.37-7.22 m, 5H), 4.5 (s, 2H),4.0-3.4 (m, 4H), 1.90-1.48 (m, 6H), 1.39-1.22 (m, 4H), 1.15-0.97 (2H),0.87 (d, 3H)

HPLC-MS: m/z=478

Example 90{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 3-phenoxypropanol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=464

Example 913-{2-[3-(2-Benzyloxy-1-methyl-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-1-methyl-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using benzyloacetone, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

HPLC-MS: m/z=492

Example 923-{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 3-phenoxypropanol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

HPLC-MS: m/z=478

Example 93{2-[3-[2-(2-Chloro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(2-chloro-phenyl)-ethanol, 4-trans-methyl-cyclohexylamineand (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.46-7.22 (m, 5H), 4.05-3.92 (m, 1H), 3.50(s, 2H), 3.49-3.30 (m, 2H), 3.93 (t, 2H), 1.72-1.62 (m, 2H), 1.60-1.44(m, 4H), 1.38-1.22 (m, 1H), 1.12-1.00 (m, 2H), 0.87 (d, 3H)

HPLC-MS: m/z=468

Example 94{2-[3-[2-(3-Chloro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(3-chloro-phenyl)-ethanol, 4-trans-methyl-cyclohexylamineand (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.43 (s, 1H), 7.42-7.22 (m, 4H), 4.05-3.95(m, 1H), 3.50 (s, 2H), 3.49-3.30 (m, 2H), 2.79 (t, 2H), 1.75-1.55 (m,2H), 1.63-1.50 (m, 4H), 1.15-1.00 (m, 2H), 0.88 (d, 3H)

HPLC-MS: m/z=468

Example 95{2-[3-[2-(4-Chloro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(4-chloro-phenyl)-ethanol, 4-trans-methyl-cyclohexylamineand (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.43 (s, 1H), 7.38-7.28 (m, 4H), 4.07-3.92(m, 1H), 3.50 (s, 2H), 3.46-3.35 (m, 2H), 2.79 (t, 2H), 1.72-1.65 8M,2H), 1.60-1.50 (m, 4H), 1.40-1.28 (m, 1H), 1.12-0.90 (m, 2H) 0.87 (d,3H)

HPLC-MS: m/z=469

Example 96{2-[3-[2-(2-Methoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(2-methoxy-phenyl)-ethanol, 4-trans-methyl-cyclohexylamineand (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.45 (s, 1H), 7.28-7.18 (m, 2H), 7.01-6.98(m, 1H), 6.92-6.85 (m, 1H), 4.08-3.93 (m, 1H), 3.89 (s, 3H), 3.50 (s,2H), 3.40-3.30 (m, 2H), 2.80-2.74 (m, 2H), 1.73-1.68 (m, 2H), 1.62-1.52(m, 4H), 1.40-1.25 (m, 1H), 1.12-1.00 (m, 2H), 0.89 (d, 3H)

HPLC-MS: m/z=464

Example 97{2-[3-[2-(3-Methoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(3-methoxy-phenyl)-ethanol, 4-trans-methyl-cyclohexylamineand (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, CDCl₃) δ 7.29-7.19 (m, 2H), 6.90-6.82 (m, 2H),6.79-6.72 (m, 1H), 3.80 (s, 3H), 3.57-3.45 (m, 2H), 3.32 (s, 2H),2.92-2.83 (m, 2H), 1.87-1.73 (m, 4H), 1.62-1.48 (m, 2H), 1.42-1.29 (m,1H), 1.28-1.09 (m, 2H), 0.92 (d, 3H)

HPLC-MS: m/z=464

Example 98{2-[3-[2-(4-Methoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(4-methoxy-phenyl)-ethanol, 4-trans-methyl-cyclohexylamineand (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, CDCl₃) δ 7.38 (s, 1H), 7.22 (d, 2H), 6.83 (d, 2H),4.20-3.90 (m, 1H), 3.79 (s, 3H), 3.55-3.42 (m, 2H), 3.38 (s, 2H),2.90-2.80 (m, 2H), 1.85-1.72 (m, 4H), 1.62-1.48 (m, 2H), 1.40-1.05 (m,3H), 0.92 (d, 3H)

HPLC-MS: m/z=464

Example 99(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(1-phenyl-ethoxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(1-phenyl-ethoxy)-ethanol, 4-trans-methyl-cyclohexylamineand (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, CDCl₃) δ 7.39 (s, 1H), 7.37-7.22 (m, 4H), 4.43 (q, 1H),4.20-4.00 (m, 1H), 3.50-3.40 (m, 4H), 3.38 (s, 2H), 1.78-1.56 (m, 4H),1.48 (d, 3H) 1.43-1.00 (m, 5H), 0.87 (d, 3H)

HPLC-MS: m/z=478

Example 100(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2-trifluoromethylsulfanyl-benzyloxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-trifluoromethylthio-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.73-7.68 (m, 1H), 7.65-7.61 (m, 1H),7.59-7.53 (m, 1H), 7.49-7.43 (m, 1H), 7.39 (s, 1H), 4.72 (s, 2H),3.99-3.87 (m, 1H), 3.63-3.57 (m, 2H), 3.54-3.47 (m, 2H), 3.48 (s, 2H),1.71-1.46 (m, 6H), 1.36-1.23 (m, 1H), 1.10-0.96 (m, 2H), 0.86 (d, 3H)

HPLC-MS: m/z=564

Example 101{2-[3-[2-(2-Cyano-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-cyano-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.85-7.81 (m, 1H), 7.70-7.59 (m, 2H),7.53-7.46 (m, 1H), 7.39 (s, 1H), 4.69 (s, 2H), 3.99-3.87 (m, 1H),3.65-3.58 (m, 2H), 3.54-3.46 (m, 2H), 3.48 (s, 2H), 1.72-1.46 (m, 6H),1.36-1.23 (m, 1H), 1.10-0.95 (m, 2H), 0.86 (d, 3H)

HPLC-MS: m/z=489

Example 102{2-[3-[2-(4-Fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

A refluxing solution of 4-trans-methyl-cyclohexylamine hydrochloride(13.9 g, 93 mmol) and potassium carbonate (25.6 g, 186 mmol) inacetonitrile (100 mL) was added a solution of 2-(benzyloxy)-ethylbromide(20 g, 93 mmol) in acetonitrile (50 mL) over the course of 30 min. Themixture was refluxed for 2 hours before it was allowed to reach roomtemperature whereupon a solution of di-tert-butyl-dicarbonate (1M, THF,93 mL) was added. The reaction mixture was stirred at room temperaturefor 18 hous before the volatiles were removed in vacuo. The residue wasdissolved in diethyl ether (150 mL) and washed with water (2×100 mL),dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by flash chromatography (SiO₂, heptane to 10% EtOAc in heptane)to give 23.7 g of(2-benzyloxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester.

This was dissolved in abs ethanol (250 mL) and Pd/C (10%, 2.0 g) wasadded. The reaction mixture was stirred under H₂ at room temperature for4 hours before it was filtered through a pad of Celite and subsequentlyconcentrated in vacuo to give 17.5 g of(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester.

(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester (500 mg, 1.94 mmol) and 4-fluoro-2-trifluoromethyl-benzylbromide(500 mg, 2.33 mmol) in DMF (10 mL) was added NaH (60% in mineral oil,155 mg, 3.89 mmol) and the reaction mixture was stirred for 2 hours atroom temperature. The reaction mixture was divided (caution!) betweenhexane (50 mL) and water (50 mL). The aqueous phase was extracted twicewith hexane (50 mL) and the combined organic fractions were dried(MgSO₄) and concentrated in vacuo. The residue was stirred in a mixtureof dichloromethane (5 mL) and trifluoroacetic acid (5 mL) for 2 hoursbefore the volatiles were removed in vacuo. The residue was purified byprep. HPLC to give 500 mg of[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-(4-trans-methyl-cyclohexyl)-amine.

{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid was prepared as described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidfrom[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-(4-trans-methyl-cyclohexyl)-amineand 5-amino-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.78-7.22 (m, 1H), 7.65-7.59 (m, 1H),7.55-7-48 (m, 1H), 7.40 (s, 1H), 4.65 (s, 2H), 4.00-3.87 (m, 1H),3.62-3.55 (m, 2H), 3.54-3.48 (m, 2H), 3.48 (s, 2H), 1.72-1.45 (m, 6H),1.38-1.18 (m, 1H), 1.10-0.95 (m, 2H), 0.87 (d, 3H)

HPLC-MS: m/z=550

Example 103{2-[3-[2-(4-Fluoro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(4-fluoro-phenyl)-ethanol, 4-trans-methyl-cyclohexylamineand (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, CDCl₃) δ 7.28-7.22 (m, 3H), 7.02-6.95 (m, 2H),4.15-3.80 (m, 1H), 3.52-3.40 (m, 2H), 3.33 (s, 2H), 2.92-2.83 (m, 2H),1.83-1.72 (m, 4H), 1.60-1.43 (m, 2H), 1.43-1.10 (m, 3H), 0.92 (d, 3H)

HPLC-MS: m/z=452

Example 104{2-[3-[2-(2-Fluoro-6-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-fluoro-6-trifluoromethyl-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=550

Example 105{2-[3-(4-trans-methyl-cyclohexyl)-3-(2-phenyl-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-phenyl-propan-1-ol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, CDCl₃) δ 7.32-7.12 (m, 6H), 3.85-3.70 (m, 1H),3.65-3.55 (m, 1H), 3.35 (s, 2H), 3.30-3.08 (m, 2H), 1.80-1.00 (m, 12H,with following distinct signal; 1.31 (d, 3H)), 0.88 (d, 3H)

HPLC-MS: m/z=448

Example 106{2-[3-[2-(2-Chloro-4-fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-chloro-4-fluoro-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.83-7.76 (m, 1H), 7.71-7.67 (m, 1H), 7.65(s, 1H), 7.48-7.40 (m, 1H), 4.82 (s, 2H), 4.24-4.12 (m, 1H), 3.88-3.80(m, 2H), 3.78-3.72 (m, 2H), 3.73 (s, 2H), 1.98-1.47 (m, 8H), 1.37-1.20(m, 2H), 1.11 (d, 3H)

HPLC-MS: m/z=517

Example 107{2-[3-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 3,4-dimethoxy-phenyl-ethanol, 4-trans-methyl-cyclohexylamineand (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, CDCl₃) δ 7.27 (s, 1H), 6.82-6.76 (m, 3H), 3.88 (s, 3H),3.86 (s, 3H), 3.54-3.44 (m, 2H), 3.32 (s, 2H), 2.89-2.80 (m, 2H),1.85-1.72 (m, 4H), 1.62-1.48 (m, 2H), 1.42-1.10 (m, 3H), 0.92 (d, 3H)

HPLC-MS: m/z=494

Example 108{2-[3-(4-trans-methyl-cyclohexyl)-3-(2-p-tolyl-ethyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 4-methyl-phenyl-ethanol, 4-trans-methyl-cyclohexylamine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, CDCl₃) δ 7.26 (s, 1H), 7.18 (d, 2H); 7.11 (d, 2H),4.3-3.8 (m, 1H), 3.52-3.43 (m, 2H), 3.32 (s, 2H), 2.90-2.82 (m, 2H),2.32 (s, 3H), 1.87-1.72 (m, 4H), 1.62-1.47 (m, 2H), 1.42-1.10 (m, 3H),0.92 (d, 3H)

HPLC-MS: m/z=448

Example 109{2-[3-(4-trans-methyl-cyclohexyl)-3-(2-pentafluorophenylmethoxy-ethyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 1,2,3,4,5-pentafluoro-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=554

Example 110(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(4-trifluoromethyl-phenyl)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 4-trifluoromethyl-phenyl-ethanol,4-trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-aceticacid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.67 (d, 2H), 7.52 (d, 2H), 7.43 (s, 1H),4.05-3.92 (m, 1H), 3.50 (s, 2H), 3.50-3.42 (m, 2H), 2.92-2.85 (m, 2H),1.73-1.65 (m, 2H), 1.62-1.50 (m, 4H), 1.40-1.25 (m, 1H), 1.13-0.98 (m,2H), 0.87 (d, 3H)

HPLC-MS: m/z=502

Example 111{2-[3-[2-(4-Ethoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(4-ethoxy-phenyl)-ethanol, 4-trans-methyl-cyclohexylamineand (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (s, 1H), 7.18 (d, 2H), 6.85 (d, 2H),4.03-3.92 (m, 3H), 3.50 (s, 2H), 3.42-3.40 (m, 2H), 2.75-2.67 (m, 2H),1.73-1.63 (m, 2H), 1.62-1.59 (m, 4H), 1.39-1.28 (m, 4H), 1.12-1.00 (m,2H), 0.87 (d, 3H)

HPLC-MS: m/z=478

Example 112{2-[3-[2-(4-Isopropoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(4-isopropoxy-phenyl)-ethanol,4-trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-aceticacid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.43 (s, 1H), 7.17 (d, 2H), 6.83 (d, 2H),4.57 (h, 1H), 4.02-3.90 (m, 1H), 3.49 (s, 2H), 3.49-3.30 (m, 2H),2.73-2.65 (m, 2H), 1.73-1.63 (m, 2H), 1.62-1.48 (m, 4H), 1.39-1.29 (m,1H), 1.25 (d, 6H), 1.12-1.00 (m, 2H), 0.87 (d, 3H)

HPLC-MS: m/z=492

Example 113(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(4-propoxy-phenyl)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(4-propoxy-phenyl)-ethanol, 4-trans-methyl-cyclohexylamineand (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.43 (s, 1H), 7.18 (d, 2H), 6.87 (d, 2H),4.05-3.93 (m, 1H), 3.88 (t, 2H), 3.50 (s, 2H), 3.42-3.30 (m, 2H),2.75-2.67 (m, 2H), 1.75-1.63 (m, 4H), 1.62-1.48 (m, 4H), 1.40-1.28 (m,1H), 1.13-1.00 (m, 2H), 0.98 (t, 3H), 0.87 (d, 3H)

HPLC-MS: m/z=492

Example 114{2-[3-[2-(2-Fluoro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(2-fluoro-phenyl)-ethanol, 4-trans-methyl-cyclohexylamineand (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.43 (s, 1H), 7.40-7.32 (m, 1H), 7.32-7.22(m, 1H), 7.19-7.12 (m, 2H), 4.06-3.94 (m, 1H), 3.50 (s, 2H), 3.47-3.38(m, 2H), 2.88-2.80 (m, 2H), 1.73-1.62 (m, 2H), 1.62-1.42 (m, 4H),1.38-1.22 (m, 1H), 1.13-0.97 (m, 2H), 0.88 (d, 3H)

HPLC-MS: m/z=452

Example 115{2-[3-[2-(3-Fluoro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(3-fluoro-phenyl)-ethanol, 4-trans-methyl-cyclohexylamineand (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMDO-d₆) δ 7.42 (s, 1H), 7.38-7.30 (m, 1H), 7.19-7.10(m, 2H), 7.08-7.00 (m, 1H), 4.05-3.93 (m, 1H), 3.49 (s, 2H), 3.48-3.39(m, 2H), 2.83-2.77 (m, 2H), 1.73-1.65 (m, 2H), 1.62-1.50 (m, 4H),1.42-1.29 (m, 1H), 1.15-0.98 (m, 2H), 0.88 (d, 3H)

HPLC-MS: m/z=452

Example 116{2-[3-[2-(4-Isopropyl-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(3-isopropyl-phenyl)-ethanol,4-trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-aceticacid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.43 (s, 1H) 7.22-7.15 (m, 4H), 4.03-3.90(m, 1H), 3.50 (s, 2H), 3.45-3.35 (m, 2H), 2.85 (h, 1H), 2.78-2.70 (m,2H), 1.72-1.64 (m, 2H), 1.63-1.48 (m, 4H), 1.39-1.26 (m, 1H), 1.18 (d,6H), 1.13-0.98 (m, 2H), 0.87 (d, 3H)

HPLC-MS: m/z=476

Example 117{2-[3-[2-(3-Fluoro-4-methoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(3-fluoro-4-methoxy-phenyl)-ethanol,4-trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-aceticacid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.43 (s, 1H), 7.20-7.13 (m, 1H), 7.12-7.00(m, 2H), 4.04-3.93 (m, 1H), 3.80 (s, 3H), 3.50 (s, 2H), 3.43-3.32 (m,2H), 2.78-2.68 (m, 2H), 1.73-1.64 (m, 2H), 1.63-1.50 (m, 4H), 1.42-1.28(m, 1H), 1.12-0.98 (m, 2H), 0.87 (d, 3H)

HPLC-MS: m/z=489

Example 118{2-[3-[2-(3-Fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 3-fluoro-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 7.39-7.33 (m, 1H), 7.18-7.05(m, 3H), 4.55 (s, 2H), 3.99-3.85 (m, 1H), 3.60-3.45 (m, 6H with tofollowing distinct signal (3.49 (s, 2H))

HPLC-MS: m/z=482

Example 119(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(3-trifluoromethyl-benzyloxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 3-trifluoromethyl-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.70-7.52 (m, 4H), 7.39 (s, 1H), 4.63 (s,2H), 3.98-3.86 m, 1H), 3.62-3.55 (m, 2H), 3.55-33.48 (m, 2H), 3.48 (s,2H), 1.72-1.62 (m, 2H), 1.62-1.47 (m, 4H), 1.40-1.22 (m, 1H), 1.11-0.96(m, 2H), 0.87 (d, 3H)

HPLC-MS: m/z=532

Example 120{2-[3-[2-(4-Methanesulfonyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 4-methylsulfonyl-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=532

Example 121(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(4-trifluoromethyl-benzyloxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 4-trifluoromethyl-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=532

Example 122(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2-trifluoromethyl-benzyloxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-trifluoromethyl-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.74-7.18 (m, 2H), 7.68-7.58 (m, 1H),7.53-7.47 (m, 1H), 7.40 (s, 1H), 4.69 (s, 2H), 4.00-3.88 (m, 1H),3.65-3.57 (m, 2H) 3.57-3.49 (m, 2H), 3.49 (s, 2H), 1.72-1.63 (m, 2H),1.62-1.47 (m, 4H), 1.38-1.20 (m, 1H), 1.10-0.97 (m, 2H), 0.87 (sd, 3H)

HPLC-MS: m/z=532

Example 123{2-[3-[2-(2-Methoxy-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-methoxy-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 7.28-7.20 (m, 1H), 6.92-6.87(m, 2H), 6.85-6.80 (m, 1H), 4.50 (s, 2H), 3.98-3.85 (m, 1H), 3.8-3.4 (m,9H, with the following distinct signals; 3.72 (s) and 3.50 (s)),1.72-1.62 (m, 2H), 1.62-1.42 (m, 4H), 1.38-1.20 (m, 1H), 1.10-0.93 (m,2H), 0.88 (d, 3H)

HPLC-MS: m/z=494

Example 124{2-[3-[2-(4-tert-Butyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 4-tert-butyl-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=520

Example 125(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(4-trifluoromethoxy-benzyloxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 4-trifluoromethoxy-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=548

Example 126{2-[3-[2-(2,4-Difluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2,4-difluoro-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=500

Example 127{2-[3-[2-(4-Isopropyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 3-isopropyl-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 7.28-7.13 (m, 4H), 4.49 (s,2H), 3.98-3.35 (M, 1H), 3.6-3.3 (m, 4H with the following distinctsignal; 3.50 (s, 2H), 2.87 (h, 1H), 1.72-1.60 (m, 2H), 1.60-1.39 (m,4H), 1.37-1.22 (m, 1H), 1.19 (d, 6H), 1.10-0.94 (m, 2H), 0.85 (d, 3H)

HPLC-MS: m/z=506

Example 128{2-[3-[2-(4-Fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 4-fluoro-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=482

Example 129(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(3-trifluoromethoxy-benzyloxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 3-trifluoromethyl-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.50-6.17 (m, 5H, with the followingdistinct signal; 7.40 (s, 1H), 4.59 (s, 2H), 3.99-3.85 (m, 1H),3.60-3.55 (m, 2H), 3.55-3.45 (m, 4H with the following distinct signal;3.49 (s, 2H), 1.72-1.63 (m, 2H), 1.63-1.45 (m, 4H), 1.39-1.22 (m, 1H),1.10-0.95 (m, 2H), 0.78 (d, 3H)

HPLC-MS: m/z=548

Example 130{2-[3-[2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-fluoro-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.48-7.30 (m, 3H, with the followingdistinct signal; 7.40 (s, 1H)), 7.21-7.13 (m, 2H), 4.58 (s, 2H),3.98-3.83 (m, 1H), 3.60-3.54 (m, 4H, with the following distinct signal3.49 (s, 2H)), 1.72-1.63 (m, 2H), 1.62-1.38 (m, 4H), 1.38-1.20 (m, 1H),1.10-0.94 (m, 2H), 0.87 (d, 3H)

HPLC-MS: m/z=482

Example 131{2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-chloro-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.52-7.49 (m, 1H), 7.47-7.41 (m, 1H), 7.40(s, 1H), 7.34-7.28 (m, 2H), 4.60 (s, 2H), 4.00-3.87 (m, 1H), 3.64-3.58(m, 2H), 3.50-3.50 (m, 2H), 3.49 (s, 2H), 1.73-1.46 (m, 6H), 1.40-1.20(m, 1H), 1.12-0.95 (m, 2H), 0.87 (d, 3H)

HPLC-MS: m/z=499

Example 132{2-[3-[2-(2,3-Difluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2,3-difluoro-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.42-7.12 (m, 4H), 4.62 (s, 2H), 3.98-3.85(m, 1H), 3.62-3.30 (m, 6H) with the following distinct signal: 3.47(s)), 1.73-1.62 (m, 2H), 1.62-1.20 (m, 5H), 1.12-0.95 (m, 2H), 0.88 (d,3H)

HPLC-MS: m/z=500

Example 133{2-[3-[2-(2,6-Difluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2,6-difluoro-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=500

Example 134{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

4-Trans-methyl-cyclohexylamine (6.65 g, 44.4 mmol) and potassiumcarbonate (12.3 g, 88.8 mmol) in acetonitrile (50 mL) was heated toreflux before a solution of (3-bromo-propoxymethyl)-benzene (10.2 g,44.4 mmol) in acetonitrile (25 mL) over a period of 30 min. The reactionmixture was refluxed for 2 hours before the solvent was removed invacuo. The residue was divided between diethyl ether (100 mL) andaqueous sodium hydroxide (1N, 50 mL). The organic phase was dried(MgSO₄), filtered and concentrated in vacuo. The residue was purifiedusing column chromatography (SiO₂, heptane-ethyl acetate 1:1) to give8.4 g (3-benzyloxy-propyl)-(4-methyl-cyclohexyl)-amine. To this wasadded a solution of bis-tert-butyl-dicarbonate (32 mmol, 1N in THF) andthe reaction mixture was stirred at room temperature for 18 hours beforethe solvent was removed in vacuo. The residue was dissolved in diethylether (150 mL) and washed with water (2×100 mL). The organic phase wasdried (MgSO₄), filtered and concentrated in vacuo to give 10.6 g of(3-benzyloxy-propyl)-(4-methyl-cyclohexyl)-carbamic acid tert-butylester. This was subsequently dissolved ethanol (100 mL) and Pd/C (10%, 1g) was added. The reaction mixture was stirred under H₂ (1 atm) for 4hours. The reaction mixture was filtered throughout a pad of celite andconcentrated in vacuo to give 7.9 g of(3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acid tert-butyl ester.

2-Methyl-phenol (147 mg, 1.36 mmol), triphenylphosphine polystyrene(0.67 g, 3 mmol/g) and diethyl azodicarboxylate (DEAD) (261 mg, 1.5mmol) in THF was stirred at room temperature for 16 hours before thesolid was filtered off. Trifluoro acetic acid (1.5 mL) was added and thereaction mixture was stirred for 1 hour before sodium hydroxide (10%, 5mL) was added. The mixture was extracted with diethyl ether (3×5 mL),the organic phase dried over MgSO₄, filtered and the solvent was removedin vacuo to give (4-trans-methyl-cyclohexyl)-(3-o-tolyloxy-propyl)-amine

{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid was prepared from(4-trans-methyl-cyclohexyl)-(3-o-tolyloxy-propyl)-amine and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester using theprocedure described for the synthesis of[2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid.

HPLC-MS: m/z=478

Example 135{2-[3-[3-(4-Methoxy-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using (3-hydroxy-propyl)-(4-methylcyclohexyl)-carbamic acidtert-butyl ester, 4-methoxy-phenol and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=494

Example 136{2-[3-[3-(4-Fluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using (3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acidtert-butyl ester, 4-fluoro-phenol and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=482

Example 137{2-[3-[3-(Indan-5-yloxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using (3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acidtert-butyl ester, indane-5-ol and (2-amino-thiazol-5-ylsulfanyl)-aceticacid ethyl ester.

HPLC-MS: m/z=504

Example 138{2-[3-[3-(3,4-Difluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using (3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acidtert-butyl ester, 3,4-difluorophenol and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=500

Example 139{2-[3-[3-(2,4-Difluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using (3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acidtert-butyl ester, 2,4-difluorophenol and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=500

Example 140{2-[3-[3-(4-tert-Butyl-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using (3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acidtert-butyl ester, 4-tert-butylphenol and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=520

Example 141{2-[3-[3-(4-Isopropyl-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using (3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acidtert-butyl ester, 4-iso-propylphenol and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=506

Example 142{2-[3-[3-(3-Acetylamino-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using (3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acidtert-butyl ester, 3-acetylaminophenol and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=521

Example 143{2-[3-[3-(2-Fluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using (3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acidtert-butyl ester, 2-fluorophenol and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (bs, 1H), 7.25-7.09 (m, 3H), 6.97-6.90(m, 1H), 4.09 (t, 2H), 4.05-3.93 (m, 1H), 3.48 (s, 2H), 3.42-3.32 (m,2H), 2.02-1.90 (m, 2H), 1.73-1.44 (m, 6H), 1.35-1.21 (m, 1H), 1.12-0.97(m, 2H), 0.87 (d, 3H)

HPLC-MS: m/z=482

Example 144{2-[3-[3-(3-Isopropyl-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using (3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acidtert-butyl ester, 2-iso-propoxyphenol and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=506

Example 145{2-[3-[3-(Benzo[1,3]dioxol-5-yloxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using (3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acidtert-butyl ester, benzo[1,3]dioxol-5-ol and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=508

Example 146(2-{3-(4-trans-methyl-cyclohexyl)-3-[3-(4-trifluoromethoxy-phenoxy)-propyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using (3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acidtert-butyl ester, 4-trifluoromethoxyphenyl and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=548

Example 147(2-{3-(4-trans-methyl-cyclohexyl)-3-[3-(3-trifluoromethoxy-phenoxy)-propyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using (3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acidtert-butyl ester, 3-trifluoromethoxyphenyl and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=548

Example 148{2-[3-[3-(3-Fluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using (3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acidtert-butyl ester, 3-fluorophenol and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=482

Example 1493-{2-[3-[3-(2-Chloro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using (3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acidtert-butyl ester, 2-chlorophenol and(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.43 (dd, 1H), 7.40 (s, 1H), 7.33-7.27 (m,1H), 7.17-7.13 (m, 1H), 6.98-6.93 (m, 1H), 4.10 (t, 2H), 4.07-3.96 (m,1H), 3.45-3.38 (m, 2H), 2.84 (t, 2H), 2.49 (t, 2H), 2.02-1.93 (m, 2H),1.71-1.46 (6H), 1.35-1.25 (m, 1H), 1.11-0.97 (m, 2H), 0.87 (d, 3H)

HPLC-MS: m/z=512

Example 1503-{2-[3-[3-(4-Chloro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described for the synthesis of{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using (3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acidtert-butyl ester, 4-chlorophenol and(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 7.32 (d, 2H)), 6.98 (d, 2H),4.01 (t, 2H), 4.00-3.93 (m, 1H), 3.47-3.27 (m, 2H), 2.84 (t, 2H), 2.49(t, 2H), 1.99-1.87 (m, 2H), 1.73-1.42 (m, 6H), 1.38-1.22 (1H), 1.12-0.96(m, 2H), 0.87 (d, 3H)

HPLC-MS: m/z=512

Example 151 {2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid

(General Procedure (A) and (B))

Preparation of Secondary Amine

Preparation ofcyclopentylmethyl-(3,4-difluoro-phenyl)-amine-3,4-Difluoroaniline (18.5mmol) dissolved in 50 ml of THF:MeOH (1:1) was addedcyclopentanecarbaldehyde (20.4 mmol) and 3 Å molsieves (5 g) and stirredfor 0.5 h at RT. Then NaBH₃CN (37.1 mmol=2 eqv.) was added and thereaction mixture was stirred for 13H at room temperature before it wasfiltered and the filtrate was concentrated in vacuo to give crudecyclopentylmethyl-(3,4-difluoro-phenyl)-amine.

Coupling:

To a solution of (2-amino-thiazol-4-yl)-acetic acid ethyl ester (1.0mmol) and cyclopentylmethyl-(3,4-difluoro-phenyl)-amine (1.0 mmol) indry toluene (10 mL) was added CDI (1.5 mmol) and DMAP (0.05 mmol). Themixture was stirred at 60° C. for 3H an then evaporated to dryness invacuo. The crude product was purified on silica gel (gradient, fromheptane:ethyl acetate (10:1) to heptane:ethyl acetate (3:1)) to give{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid ethyl ester.

Hydrolysis:

{2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid ethyl ester (0.5 mmol) was dissolved in dioxane (2 mL) and treatedwith 1N NaOH (2 mL) for 1H at room temperature. Dioxane was removed byevaporation. Addition of 1N HCl to pH 1 caused precipitation. Theprecipitate was isolated by filtration, washed with water and dried togive the title compound as crystals.

¹H NMR (400 MHz, DMSO-d₆) δ 7.42-7.53 (m, 1H), 7.11-7.22 (m, 1H), 6.75(s, 1H), 3.67 (d, 1H), 3.50 (s, 1H), 1.87-2.01 (m, 1H), 1.51-1.65 (m,3H), 1.39-1.50 (m, 1H), 1.11-1.21 (m, 1H)

HPLC-MS: m/z=396, R_(t)=1.9 min

Example 152 {2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid

Preparation of (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester

5-Bromo-2-aminothiazole (25 g, 96 mmol) and K₂CO₃ (26.5 g, 192 mmol) wassuspended in DMF (50 mL) and stirred to 0° C. Ethyl thioglycolate (11.6mL, 96 mmol) was added during 10 min. The reaction mixture was allowedto reach room temperature and stirred for further 13H. Addition of water(100 mL) and EtOAc (150 mL). Separation of the organic phase followed byextraction of the aqueous phase with EtOAc (2×100 mL). The combinedorganic phases were washed with aqueous NaHCO₃ (2000 mL), brine (2×200mL) and dried (MgSO₄), filtered and evaporated. The crude product wasdissolved in a small amount of DCM and purified by flash chromathography(ISCO 330 g silica column, eluent A: heptane/B: 2% TEA in EtOAc.Gradient from 30% B->100% B.) to give 50-65% pure(2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester as a dark red-brownoil.

¹H NMR (CDCl₃): δ 7.16 (s, 1H), 5.45 (bs, 2H), 4.26 (q, 2H), 3.39 (s,2H), 1.28 (t, 3H).

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using 3,4-difluoroaniline, cyclopentanecarbaldehyde and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.44-7.55 (m, 1H), 7.38 (s, 1H), 7.14-7.23(m, 1H), 3.68 (d, 1H), 3.47-3.53 (m, 1H), 1.88-1.99 (m, 1H), 1.53-1.64(m, 3H), 1.41-1.50 (m, 1H), 1.12-1.21 (m, 1H)

HPLC-MS: m/z=428, R_(t)=2.5 min

Example 153 2-{2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionicacid

Preparation of 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acidethyl ester

Step 1:

2-Aminothiazole (35 g, 350 mmol) and sodium thiocyanate (89 g, 1.08 mol)in MeOH (400 mL) was stirred at −10° C. Bromine (18.0 mL, 350 mmol)dissolved in MeOH (100 mL) saturated with NaBr was slowly added keepingthe internal temperature between −10 and 0° C. After the addition themixture was stirred at 0° C. for 3H and the reaction mixture was pouredinto ice water (1500 mL). Aqueous NH₄OH was added to pH ca 8.5 causingprecipitation of light yellow crystals which were isolated byfiltration, washed with ice water and dried in a vacuum oven to give 30g (55%) 5-thiocyanato-thiazol-2-ylamine as light yellow crystals.

Step 2:

In a nitrogen atmosphere 5-thiocyanato-thiazol-2-ylamine (10 g, 64 mmol)dissolved in MeOH (300 mL) was added 2,3-dihydroxy-1,4-dithiolbutane(DTT, 9.8 g, 64 mmol) and stirred at room temperature for 1½ h. Then2-bromo-2-methyl-propionic acid ethyl ester (13.6 g, 70 mmol) and K₂CO₃(10.5 g, 76 mmol) was added and the reaction mixture was stirred forfurther 13H. Addition of water (500 mL) and EtOAc (500 mL). Separationof the organic phase followed by extraction of the aqueous phase withEtOAc (2×300 mL). The combined organic phases were washed with water(500 mL) and brine (2×400 mL) and dried (MgSO₄), filtered andevaporated. The crude product was dissolved in a small amount of DCM andpurified by flash chromathography (heptane/EtOAc 2:1->1:2). Fractionscontaining the product were pooled and evaporated to a productcontaining impurities of DDT. This product was dissolved in diethylether (100 mL) and washed with water several times. The ether phase wasdried (MgSO₄), filtered and evaporated to give 8.45 g (54%) of 95% pure2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester aslight brown crystals.

The title compound was prepared via2-{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionicacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using 3,4-difluoroaniline, cyclopentanecarbaldehyde and2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.46-7.57 (m, 1H), 7.37 (s, 1H), 7.17-7.26(m, 1H), 3.68 (d, 1H), 1.88-1.99 (m, 1H), 1.53-1.64 (m, 3H), 1.41-1.49(m, 1H), 1.39 (s, 3H), 1.12-1.21 (m, 1H)

HPLC-MS: m/z=456, R_(t)=2.2 min

Example 154 2-({2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonyl}-methyl-amino)-N,N-diethyl-acetamide

Preparation of2-[(2-Amino-thiazole-5-sulfonyl)-methyl-amino]-N,N-diethyl-acetamide

A mixture of N,N-diethyl-2-methylamino-acetamide (12 mmol),2-acetylamino-thiazole-5-sulfonyl chloride (12 mmol) (prepared asdescribed in J. Am. Chem. Soc 69, 2063, 1947), DIPEA (15 mmol) in DCM(50 mL) was stirred at room temperature over night. The reaction mixturewas diluted with DCM (50 mL) washed with 10% aq NaHSO4, water and brine,dried and concentrated to give2-[(2-acetylamino-thiazole-5-sulfonyl)-methyl-amino]-N,N-diethyl-acetamide(59%) as pale yellow crystals. This was suspended in EtOH (10 mL) andadded 8N HCl in dioxane (10 mL) and heated for 3H at 80° C. and thencooled to room temperature and concentrated in vacuo to give2-[(2-amino-thiazole-5-sulfonyl)-methyl-amino]-N,N-diethyl-acetamide asa hydrochloride as colourless crystals.

The title compound was prepared as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using 3,4-difluoroaniline, cyclopentanecarbaldehyde and2-[(2-amino-thiazole-5-sulfonyl)-methyl-amino]-N,N-diethyl-acetamide asa hydrochloride.

¹H NMR (300 MHz, CDCl₃) δ 7.73 (s, 1H), 7.28-7.39 (m, 1H), 7.07-7.21 (m,1H), 3.95 (s, 1H), 3.71 (d, 1H), 3.30-3.43 (m, 3H), 2.91 (s, 3H),1.98-2.11 (m, 1H), 1.49-1.76 (m, 3H), 1.24-1.33 (m, 3H), 1.24 (t, 3H),1.11 (t, 3H), 0.81-0.95 (m, 1H)

HPLC-MS: m/z=544, R_(t)=2.2 min

Example 155 (S)-1-{2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonyl}-pyrrolidine-2-carboxylicacid

(General Procedure (A), (B) and (H))

Step 1.

A mixture of L-proline methylester hydrochloride (15 mmol),2-acetylamino-thiazole-5-sulfonyl chloride (12 mmol) (prepared asdescribed in J. Am. Chem. Soc 69, 2063, 1947), DIPEA (35 mmol) in DCM(50 mL) was stirred at room temperature over night. Addition of waterand 1N HCl to pH 2. Isolation of the organic phase which was washed withwater and brine, dried and concentrated to give(S)-1-(2-acetylamino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acidmethyl ester as brown crystals. These were suspended in EtOH (15 mL) andadded 4N HCl in dioxane (15 mL) and heated for 3H at 80° C. and thencooled to room temperature. Addition of aqueous NaHCO₃ to neutral pH.The organic phase was isolated and the aqueous phase was extracted withCH₂Cl₂, and the combined organic phases were dried and concentrated invacuo to give(S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methylester as colourless crystals.

The title compound was prepared via(S)-1-{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonyl}-pyrrolidine-2-carboxylicacid methyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using 3,4-difluoroaniline, cyclopentanecarbaldehyde and(S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methylester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.92 (s, 1H), 7.48-7.60 (m, 1H), 7.19-7.29(m, 1H), 3.99-4.09 (m, 1H), 3.69 (d, 1H), 3.38-3.46 (m, 1H), 3.17-3.25(m, 1H), 1.80-2.06 (m, 3H), 1.52-1.72 (m, 3H), 1.42-1.50 (m, 1H),1.11-1.22 (m, 1H)

HPLC-MS: m/z=515, R_(t)=2.1 min

Example 156 {2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonylamino}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonylamino}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using 3,4-difluoroaniline, cyclopentanecarbaldehyde and(2-amino-thiazole-5-sulfonylamino)-acetic acid ethyl ester the latterprepared in a similar manner as(S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methylester.

¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (t, 1H), 7.76 (s, 1H), 7.48-7.59 (m,1H), 7.16-7.27 (m, 1H), 3.69 (d, 1H), 3.63 (d, 1H), 1.87-2.00 (m, 1H),1.53-1.65 (m, 3H), 1.40-1.51 (m, 1H), 1.12-1.23 (m, 1H)

HPLC-MS: m/z=475, R_(t)=1.9 min

Example 157 3-{2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonylamino}-propionicacid

The title compound was prepared via3-{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonylamino}-propionicacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using 3,4-difluoroaniline, cyclopentanecarbaldehyde and3-(2-amino-thiazole-5-sulfonylamino)-propionic acid ethyl ester thelatter prepared in a similar manner as(S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methylester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.84 (t, 1H), 7.78 (s, 1H), 7.57 (s, 1H),7.49 (dd, 1H), 7.19-7.25 (m, 1H), 3.69 (d, 1H), 2.97-3.04 (m, 1H), 2.41(t, 1H), 1.89-1.99 (m, 1H), 1.54-1.65 (m, 3H), 1.41-1.50 (m, 1H),1.12-1.21 (m, 1H)

HPLC-MS: m/z=489, R_(t)=1.9 min

Example 158 {2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid

(General Procedure (C) and (A))

Preparation of Secondary Amine Preparation ofcyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine Step 1

4-(Methanesulfonyl)aniline hydrochloride (19 mmol) suspended in 25 mL ofEt2O was added Et3N (48 mmol) and then a solution cyclopentanecarbonylchloride (19 mmol) in 25 mL of Et2O was added dropwise during in 10 min.The reaction mixture was stirred for 3 h at RT and then diluted withEtOAc (100 mL) washed with 1N aq HCl, water and aq sat NaHCO₃. Theorganic phase was dried and concentrated in vacuo to give crudecyclopentanecarboxylic acid (4-methanesulfonyl-phenyl)-amide which wasused without further purification.

Step 2:

In a nitrogen atmosphere a solution of cyclopentanecarboxylic acid(4-methanesulfonyl-phenyl)-amide (10 mmol) in THF (20 mL) was added asolution of 1M BH3 in THF (20 mL). The mixture was refluxed for 3H andcooled to RT. Addition of 10 mL of MeOH followed by reflux for 15 min.The mixture was cooled and added water (100 mL) and EtOAc (200 mL). Theorganic phase was isolated and washed with 1N NaOH, water and brine,dried (MgSO4), filtered and concentrated in vacuo to affordcyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine as a yellow solid.

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid ethyl ester employing the coupling and hydrolysis protocol used forthe synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and(2-amino-thiazol-4-yl)-acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (s, 1H), 7.58 (d, 1H), 6.76 (s, 1H),3.81 (d, 1H), 3.51 (s, 1H), 3.25 (s, 3H), 1.91-2.01 (m, 1H), 1.51-1.62(m, 3H), 1.39-1.49 (m, 1H), 1.11-1.23 (m, 1H)

HPLC-MS: m/z=438, R_(t)=1.6 min

Example 159 {2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (d, 1H), 7.58 (d, 1H), 7.39 (s, 1H),3.81 (d, 1H), 3.51 (s, 1H), 3.26 (s, 3H), 1.90-2.01 (m, 1H), 1.52-1.62(m, 3H), 1.40-1.49 (m, 1H), 1.13-1.23 (m, 1H)

HPLC-MS: m/z=470, R_(t)=1.7 min

Example 160 2-{2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionicacid

The title compound was prepared via2-{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionicacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.94 (d, 1H), 7.59 (d, 1H), 7.38 (s, 1H),3.81 (d, 1H), 3.26 (s, 3H), 1.90-2.01 (m, 1H), 1.52-1.63 (m, 3H), 1.40(s, 3H), 1.37-1.48 (m, 1H), 1.13-1.24 (m, 1H)

HPLC-MS: m/z=498, R_(t)=1.9 min

Example 161 (S)-1-{2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazole-5-sulfonyl}-pyrrolidine-2-carboxylicacid

The title compound was prepared via(S)-1-{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazole-5-sulfonyl}-pyrrolidine-2-carboxylicacid methyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and(S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methylester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (d, 1H), 7.92 (s, 1H), 7.62 (d, 1H),4.04 (dd, 1H), 3.82 (d, 1H), 3.37-3.46 (m, 1H), 3.26-3.28 (m, 3H),3.18-3.25 (m, 1H), 1.80-2.08 (m, 3H), 1.65-1.76 (m, 1H), 1.52-1.64 (m,3H), 1.40-1.50 (m, 1H), 1.12-1.23 (m, 1H)

HPLC-MS: m/z=557, R_(t)=1.8 min

Example 162 {2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazole-5-sulfonylamino}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazole-5-sulfonylamino}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and(2-amino-thiazole-5-sulfonylamino)-acetic acid ethyl ester the latterprepared in a similar manner as(S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methylester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (d, 1H), 7.76 (s, 1H), 7.61 (d, 1H),3.82 (d, 1H), 3.63 (s, 1H), 3.27 (s, 3H), 1.89-2.02 (m, 1H), 1.52-1.63(m, 3H), 1.40-1.49 (m, 1H), 1.13-1.24 (m, 1H)

HPLC-MS: m/z=517, R_(t)=1.6 min

Example 163 3-{2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazole-5-sulfonylamino}-propionicacid

The title compound was prepared via3-{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazole-5-sulfonylamino}-propionicacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and3-(2-amino-thiazole-5-sulfonylamino)-propionic acid ethyl ester thelatter prepared in a similar manner as(S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methylester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (d, 1H), 7.86 (t, 1H), 7.78 (s, 1H),7.62 (d, 1H), 3.82 (d, 1H), 3.27 (s, 3H), 2.97-3.05 (m, 1H), 2.41 (t,1H), 1.89-2.03 (m, 1H), 1.52-1.63 (m, 3H), 1.39-1.49 (m, 1H), 1.13-1.24(m, 1H)

HPLC-MS: m/z=531, R_(t)=1.6 min

Example 164 3-{2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Preparation of 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethylester

5-Bromo-2-aminothiazole (25 g, 96 mmol) in DMF (150 mL) was added K₂CO₃(26.5 g, 192 mmol) and the mixture was purged with N₂ for 5 min. Themixture was cooled to 0° C. on an ice bath before 3-mercaptopropionicacid ethyl ester (12.9 g, 96 mmol) was added dropwise over the course of30 min. The reaction mixture was stirred for 13 Hours before water (400mL) was added. The aqueous mixture was extracted with Et₂O (1×500 mL,2×250 mL). The combined organic phases was washed with saturated NH₄Cl(3×150 mL), dried (MgSO₄). The solvent was removed in vacuo to give adark residue which was purified by column chromatography (SiO₂,EtOAc-heptane (1:1)). The solvent was removed in vacuo to give 11 g(49%) of 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

¹H NMR (400 MHz, CDCl₃) δ 7.1 (s, 1H), 5.2 (bs, 2H), 4.2 (q, 2H), 2.8(t, 2H), 2.6 (t, 2H), 1.3 (t, 3H).

The title compound was prepared via3-{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using 3,4-difluoroaniline, cyclopentanecarbaldehyde and3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) 7.43-7.55 (m, 1H), 7.37 (s, 1H), 7.15-7.22 (m,1H), 3.68 (d, 1H), 2.85 (t, 1H), 2.46-2.50 (m, 1H), 1.88-1.99 (m, 1H),1.53-1.64 (m, 3H), 1.41-1.50 (m, 1H), 1.11-1.21 (m, 1H)

HPLC-MS: m/z=422, R_(t)=2.1 min

Example 165 3-{2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

The title compound was prepared via3-{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (d, 1H), 7.58 (d, 1H), 7.37 (s, 1H),3.81 (d, 1H), 3.26 (s, 3H), 2.86 (t, 1H), 2.47-2.50 (m, 1H), 1.90-2.01(m, 1H), 1.52-1.62 (m, 3H), 1.40-1.49 (m, 1H), 1.12-1.23 (m, 1H)

HPLC-MS: m/z=484, R_(t)=1.8 min

Example 166 {2-[3-(3-Acetylamino-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-(3-acetylamino-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using N-(3-amino-phenyl)-acetamide, cyclopentanecarbaldehyde and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.06 (s, 1H), 7.58 (d, 1H), 7.47-7.51(m, 1H), 7.37 (d, 1H), 7.32 (d, 1H), 6.97 (d, 1H), 3.66 (d, 1H), 3.49(s, 1H), 2.04 (s, 3H), 1.91-2.01 (m, 1H), 1.53-1.64 (m, 3H), 1.41-1.50(m, 1H), 1.14-1.24 (m, 1H)

HPLC-MS: m/z=449, R_(t)=1.7 min

Example 167 3-{2-[3-(3-Acetylamino-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid

The title compound was prepared via3-{2-[3-(3-acetylamino-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using N-(3-amino-phenyl)-acetamide, cyclopentanecarbaldehyde and3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.07 (s, 1H), 7.57 (d, 1H), 7.50 (s,1H), 7.30-7.37 (m, 1H), 6.97 (d, 1H), 3.66 (d, 1H), 2.85 (t, 1H),2.47-2.50 (m, 1H), 2.04 (s, 3H), 1.92-2.01 (m, 1H), 1.53-1.64 (m, 3H),1.40-1.51 (m, 1H), 1.14-1.24 (m, 1H)

HPLC-MS: m/z=463, R_(t)=1.8 min

Example 168 {2-[3-Cyclopentylmethyl-3-(3-dimethylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3-dimethylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using 3-(cyclopentylmethyl-amino)-N,N-dimethyl-benzamide and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.48 (s, 1H), 7.27-7.42 (m, 3H),3.65-3.77 (m, 1H), 3.49 (s, 1H), 2.97 (s, 3H), 1.87-2.00 (m, 1H),1.51-1.62 (m, 3H), 1.40-1.48 (m, 1H), 1.12-1.23 (m, 1H).

HPLC-MS: M/Z=463, Rt=1.77 min.

Example 169 3-{2-[3-Cyclopentylmethyl-3-(3-dimethylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3-dimethylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using 3-(cyclopentylmethyl-amino)-N,N-dimethyl-benzamide and(2-amino-thiazol-5-ylsulfanyl) propionic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.44-7.51 (m, 1H), 7.30-7.40 (m, 3H),3.72 (d, 1H), 2.96 (s, 3H), 2.85 (t, 1H), (2.46-2.55, m, 2H), 1.89-1.99(m, 1H), 1.51-1.62 (m, 3H), 1.36-1.49 (m, 1H), 1.07-1.28 (m, 1H).

HPLC-MS: M/Z=477, R_(t)=1.82 min

Example 170 {2-[3-(3-Carbamoyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3-carbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using 3-(cyclopentylmethyl-amino)-benzamide and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 8.05 (s, 1H), 7.79-7.85 (m, 1H),7.43-7.52 (m, 3H), 7.38 (s, 1H), 3.73 (d, 1H), (3.33-3.4 m, 2H), 3.49(s, 1H), 1.89-1.99 (m, 1H), 1.52-1.64 (m, 3H), 1.40-1.49 (m, 1H),1.13-1.24 (m, 1H).

HPLC-MS: M/Z=435, Rt=1.65 min

Example 1713-{2-[3-(3-Carbamoyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-propionicacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3-carbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using 3-(cyclopentyl methyl-amino)-benzamide and(2-amino-thiazol-5-ylsulfanyl) propionic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 8.04 (s, 1H), 7.77-7.87 (m, 1H),7.41-7.52 (m, 3H), 7.35 (s, 1H), 3.73 (d, 1H), 2.85 (t, 1H), (2.45-2.55,m, 2H), 1.88-2.01 (m, 1H), 1.52-1.64 (m, 3H), 1.40-1.51 (m, 1H),1.09-1.27 (m, 1H).

HPLC-MS: M/Z=449, Rt=1.71 min.

Example 172 {2-[3-Cyclopentylmethyl-3-(3-methylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3-methylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using 3-(cyclopentylmethyl-amino)-N-methyl-benzamide and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 8.49 (d, 1H), 7.77-7.81 (m, 1H), 7.75(s, 1H), 7.42-7.53 (m, 1H), 7.37 (s, 1H), 3.73 (d, 1H), 3.49 (s, 1H),2.79 (d, 3H), 1.88-1.98 (m, 1H), 1.52-1.63 (m, 3H), 1.39-1.49 (m, 1H),1.11-1.23 (m, 1H).

HPLC-MS: M/Z=449, Rt=1.71 min

Example 173 3-{2-[3-Cyclopentylmethyl-3-(3-methylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3-methylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using 3-(cyclopentylmethyl-amino)-N-methyl-benzamide and(2-amino-thiazol-5-ylsulfanyl) propionic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 8.47-8.53 (m, 1H), 7.77-7.83 (m, 1H),7.75-7.77 (m, 1H), 7.42-7.54 (m, 1H), 7.35 (s, 1H), 3.73 (d, 1H), 2.85(t, 1H), 2.79 (d, 3H), 2.46-2.50 (m, 2H), 1.89-1.98 (m, 1H), 1.50-1.64(m, 3H), 1.40-1.46 (m, 1H), 1.09-1.25 (m, 1H).

HPLC-MS: M/Z=463, Rt=1.78 min

Example 174 {2-[3-Cyclopentylmethyl-3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(3-trifluoromethyl-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

HPLC-MS: M/Z=460, 2, 15 min.

Example 175 {2-[3-Cyclopentylmethyl-3-(4-sulfamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(4-sulfamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclopentylmethyl-(4-sulfamoyl-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.82 (d, 1H), 7.50 (d, 1H), 7.41 (s,1H), 7.36-7.40 (m, 1H), 3.77 (d, 1H), 3.49 (s, 1H), 1.88-1.98 (m, 1H),1.51-1.62 (m, 3H), 1.39-1.50 (m, 1H), 1.11-1.21 (m, 1H).

HPLC-MS: M/Z=471, Rt=1.63 min

Example 176 {2-[3-Cyclopentylmethyl-3-(4-fluoro-3-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(4-fluoro-3-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclopentylmethyl-(4-fluoro-3-trifluoromethyl-phenyl)-amineand (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.73-7.77 (m, 1H), 7.67-7.72 (m, 1H),7.55 (t, 1H), 7.39 (s, 1H), 3.71 (d, 1H), 3.49 (s, 1H), 1.88-1.99 (m,1H), 1.52-1.63 (m, 3H), 1.40-1.51 (m, 1H), 1.11-1.21 (m, 1H).

HPLC-MS: M/Z=478, Rt=2.19 min

Example 177 {2-[3-Cyclopentylmethyl-3-(4-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(4-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(4-trifluoromethyl-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.76 (d, 1H), 7.54 (d, 1H), 7.39 (s,1H), 3.78 (d, 1H), 3.50 (s, 1H), 1.89-1.99 (m, 1H), 1.51-1.62 (m, 3H),1.39-1.50 (m, 1H), 1.12-1.23 (m, 1H).

HPLC-MS: M/Z=457, Rt=2.18 min.

Example 178 {2-[3-Cyclopentylmethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(4-trifluoromethoxy-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.37-7.46 (m, 3H), 3.71 (d, 1H), 3.49(s, 1H), 1.88-1.98 (m, 1H), 1.52-1.63 (m, 3H), 1.40-1.51 (m, 1H),1.12-1.22 (m, 1H).

HPLC-MS: M/Z=476, Rt=2.16 min

Example 179 {2-[3-Cyclopentylmethyl-3-(3-sulfamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3-sulfamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclopentylmethyl-(3-sulfamoyl-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.68-7.76 (m, 1H), 7.57-7.62 (m, 1H),7.50-7.55 (m, 1H), 7.43 (s, 1H), 7.39 (s, 1H), 3.75 (d, 1H), 3.50 (s,1H), 1.95 (s, 1H), 1.52-1.64 (m, 3H), 1.40-1.51 (m, 1H), 1.13-1.23 (m,1H).

HPLC-MS: M/Z=471, Rt=1.63 min

Example 180 [2-(3-Benzo[1,3]dioxol-5-yl-3-cyclopentylmethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid

The title compound was prepared via[2-(3-benzo[1,3]dioxol-5-yl-3-cyclopentylmethyl-ureido)-thiazol-5-ylsulfanyl]-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using benzo[1,3]dioxol-5-yl-cyclohexylmethyl-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.36 (s, 1H), 6.91-6.96 (m, 1H), 6.76(dd, 1H), 6.08 (s, 1H), 3.60 (d, 1H), 3.48 (s, 1H), 1.89-2.00 (m, 1H),1.52-1.64 (m, 3H), 1.40-1.51 (m, 1H), 1.13-1.24 (m, 1H).

HPLC-MS: M/Z=436, R_(t)=1.96 min.

Example 181 {2-[3-Cyclopentylmethyl-3-(3-trifluoromethoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3-trifluoromethoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(3-trifluoromethoxy-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.53 (t, 1H), 7.39 (s, 1H), 7.33-7.37(m, 1H), 7.30 (d, 1H), 3.74 (d, 1H), 3.50 (s, 1H), 1.88-1.99 (m, 1H),1.51-1.62 (m, 3H), 1.39-1.50 (m, 1H), 1.10-1.21 (m, 1H).

HPLC-MS: M/Z=476, R_(t)=2.20 min

Example 182 {2-[3-Cyclopentylmethyl-3-(6-methoxy-pyridin-3-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(6-methoxy-pyridin-3-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(6-methoxy-pyridin-3-yl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 8.10 (d, 1H), 7.65 (dd, 1H), 7.37 (s,1H), 6.87 (d, 1H), 3.88 (s, 3H), 3.64 (d, 1H), 3.49 (s, 1H), 1.87-2.00(m, 1H), 1.53-1.64 (m, 3H), 1.40-1.51 (m, 1H), 1.11-1.25 (m, 1H).

HPLC-MS: M/Z=423, R_(t)=1.83 min

Example 183{2-[3-(6-Acetylamino-pyridin-3-yl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(6-acetylamino-pyridin-3-yl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using N-[5-(cyclopentylmethyl-amino)-pyridin-2-yl]-acetamide and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 10.63 (s, 1H), 8.22 (d, 1H), 8.10 (d,1H), 7.71 (dd, 1H), 7.38 (s, 1H), 3.67 (d, 1H), 3.49 (s, 1H), 2.11 (s,3H), 1.91-2.00 (m, 1H), 1.53-1.64 (m, 3H), 1.40-1.50 (m, 1H), 1.12-1.22(m, 1H).

HPLC-MS: M/Z=450, R_(t)=1.55 min

Example 184{2-[3-(3-Acetylamino-phenyl)-3-pentyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(3-acetylamino-phenyl)-3-pentyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using N-(3-amino-phenyl)-acetamide, pentanal and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 10.05 (s, 1H), 7.57 (d, 1H), 7.50 (s,1H), 7.31-7.39 (m, 1H), 6.95 (d, 1H), 3.61-3.68 (m, 1H), 3.49 (s, 1H),2.04 (s, 3H), 1.41-1.49 (m, 1H), 1.20-1.30 (m, 3H), 0.83 (t, 3H).

HPLC-MS: M/Z=437, R_(t)=1.70 min

Example 185{2-[3-(3-Acetylamino-phenyl)-3-cyclohexylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(3-acetylamino-phenyl)-3-cyclohexylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using N-(3-amino-phenyl)-acetamide, cyclohexylcarbaldehyde and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

HPLC-MS: M/Z=463, R_(t)=1.80 min

Example 186{2-[3-(3-Acetylamino-phenyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(3-acetylamino-phenyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using N-(3-amino-phenyl)-acetamide, 3-methylbutanol and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 10.05 (s, 1H), 7.57 (d, 1H), 7.47 (s,1H), 7.31-7.38 (m, 1H), 6.95 (d, 1H), 3.64-3.72 (m, 1H), 3.49 (s, 1H),2.04 (s, 3H), 1.50-1.60 (m, 1H), 1.31-1.39 (m, 1H), 0.85 (d, 3H).

HPLC-MS: M/Z=437, R_(t)=1.68 min

Example 187{2-[3-(3-Acetylamino-phenyl)-3-hexyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(3-acetylamino-phenyl)-3-hexyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using N-(3-amino-phenyl)-acetamide, hexanal and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 10.05 (s, 1H), 7.57 (d, 1H), 7.47 (s,1H), 7.30-7.39 (m, 1H), 6.94 (d, 1H), 3.59-3.69 (m, 1H), 3.49 (s, 1H),2.04 (s, 3H), 1.39-1.49 (m, 1H), 1.19-1.29 (m, 3H), 0.80-0.87 (m, 3H).

HPLC-MS: M/Z=451, R_(t)=1.83 min.,

Example 188{2-[3-(3-Acetylamino-phenyl)-3-cyclopropylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(3-acetylamino-phenyl)-3-cyclopropylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using N-(3-amino-phenyl)-acetamide, cyclopropanecarboxaldehyde and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 10.05 (s, 1H), 7.58 (d, 1H), 7.52 (s,1H), 7.30-7.39 (m, 1H), 6.97 (d, 1H), 3.55 (d, 1H), 3.49 (s, 1H), 2.04(s, 3H), 0.91-1.00 (m, 1H), 0.36-0.42 (m, 1H), 0.09-0.15 (m, 1H).

HPLC-MS: M/Z=421, R_(t)=1.47 min.

Example 189{2-[3-(3-Acetylamino-phenyl)-3-(3,3-dimethyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(3-acetylamino-phenyl)-3-(3,3-dimethyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using N-(3-amino-phenyl)-acetamide, 3,3-dimethylbutyraldehyde and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 10.05 (s, 1H), 7.59 (d, 1H), 7.45 (s,1H), 7.31-7.38 (m, 1H), 6.95 (d, 1H), 3.64-3.71 (m, 1H), 3.49 (s, 1H),2.04 (s, 3H), 1.35-1.44 (m, 1H), 0.87 (s, 9H).

HPLC-MS: M/Z=451, R_(t)=1.76 min

Example 190{2-[3-Cyclohexylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclohexylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclohexylmethyl-(3,4-difluorophenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.45-7.55 (m, 1H), 7.38 (s, 1H),7.15-7.20 (m, 1H), 3.58 (d, 1H), 3.49 (s, 1H), 1.54-1.69 (m, 3H),1.35-1.46 (m, 1H), 1.05-1.13 (m, 3H), 0.86-0.97 (m, 1H).

HPLC-MS: M/Z=442, Rt=2.16 min.

Example 191 [2-(3-Benzo[1,3]dioxol-5-yl-3-cyclohexylmethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid

The title compound was prepared via[2-(3-benzo[1,3]dioxol-5-yl-3-cyclohexylmethyl-ureido)-thiazol-5-ylsulfanyl]-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using benzo[1,3]dioxol-5-yl-cyclohexylmethyl-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.36 (s, 1H), 6.93 (s, 1H), 6.93 (d,1H), 6.76 (dd, 1H), 6.08 (s, 1H), 3.51 (d, 1H), 3.48 (s, 1H), 1.55-1.72(m, 3H), 1.35-1.46 (m, 1H), 1.06-1.17 (m, 3H), 0.87-0.97 (m, 1H).

HPLC-MS: M/Z=450, Rt=2.08 min

Example 192{2-[3-Cyclohexylmethyl-3-(6-methoxy-pyridin-3-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclohexylmethyl-3-(6-methoxy-pyridin-3-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclohexylmethyl-(6-methoxy-pyridin-3-yl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 8.09 (d, 1H), 7.64 (dd, 1H), 7.37 (s,1H), 6.87 (d, 1H), 3.88 (s, 3H), 3.54 (d, 1H), 3.49 (s, 1H), 1.55-1.71(m, 3H), 1.34-1.45 (m, 1H), 1.06-1.17 (m, 3H), 0.86-0.97 (m, 1H)

HPLC-MS: M/Z=437, Rt=1.96 min.

Example 193 {2-[3-Cyclopentylmethyl-3-(3-ethylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3-ethylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using 3-(cyclopentylmethyl-amino)-N-ethyl-benzamide and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 8.53 (t, 1H), 7.81 (d, 1H), 7.77 (s,1H), 7.42-7.56 (m, 1H), 7.37 (s, 1H), 3.73 (d, 1H), 3.49 (s, 1H),3.26-3.32 (m, 1H), 1.88-1.99 (m, 1H), 1.52-1.63 (m, 3H), 1.39-1.50 (m,1H), 1.14-1.23 (m, 1H), 1.12 (t, 3H).

HPLC-MS: M/Z=463, Rt=1.75 min.

Example 194 {2-[3-Cyclobutylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-cyclobutylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclobutylmethyl-(3,4-difluorophenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.42-7.51 (m, 1H), 7.38 (s, 1H),7.10-7.16 (m, 1H), 3.75 (d, 1H), 3.49 (s, 1H), 2.35-2.44 (m, 1H),1.83-1.92 (m, 1H), 1.71-1.82 (m, 1H), 1.55-1.65 (m, 1H).

HPLC-MS: M/Z=414, Rt=1.96 min

Example 195 {2-[3-Cyclopentylmethyl-3-(3-isopropylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3-isopropylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using 3-(cyclopentylethyl-amino)-N-isopropyl-benzamide and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 8.26 (d, 1H), 7.78-7.88 (m, 1H),7.42-7.52 (m, 1H), 7.37 (s, 1H), 4.05-4.16 (m, 1H), 3.73 (d, 1H), 3.49(s, 1H), 1.88-2.00 (m, 1H), 1.52-1.64 (m, 3H), 1.40-1.51 (m, 1H),1.18-1.24 (m, 1H), 1.17 (d, 3H)

HPLC-MS: M/Z=477, Rt=1.86 min.

Example 196 (2-{3-[3-(Azetidine-1-carbonyl)-phenyl]-3-cyclopentylmethyl-ureido}-thiazol-5-ylsulfanyl)-acetic acid

The title compound was prepared via(2-{3-[3-(azetidine-1-carbonyl)-phenyl]-3-cyclopentylmethyl-ureido}-thiazol-5-ylsulfanyl)-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using azetidin-1-yl-[3-(cyclopentylmethyl-amino)-phenyl]-methanoneand (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.47-7.55 (m, 3H), 7.42-7.45 (m, 1H),7.37 (s, 1H), 4.27-4.34 (t, 1H), 4.04 (t, 1H), 3.72 (d, 1H), 3.50 (s,1H), 2.21-2.29 (m, 1H), 1.89-1.97 (m, 1H), 1.52-1.61 (m, 3H), 1.40-1.49(m, 1H), 1.12-1.21 (m, 1H)

HPLC-MS: M/Z=475, Rt=1.74 min

Example 197{2-[3-(3,4-Difluoro-phenyl)-3-(4-methyl-cyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(3,4-difluoro-phenyl)-3-(4-methyl-cyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using 4-methyl-cyclohexylmethyl-(3,4-difluorophenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

HPLC-MS: M/Z=456, Rt=2.29 min

Example 198{2-[3-(3,4-Difluoro-phenyl)-3-(4-trifluoromethyl-cyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(3,4-difluoro-phenyl)-3-(4-trifluoromethyl-cyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using4-trifluoromethyl-cyclohexylmethyl-(3,4-difluorophenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.51-7.58 (m, 1H), 7.44-7.49 (m, 1H),7.38 (s, 1H), 7.17-7.23 (m, 1H), 3.78 (d, 1H), 3.50 (s, 1H), 2.18-2.30(m, 1H), 1.65-1.73 (m, 1H), 1.39-1.64 (m, 8H)

HPLC-MS: M/Z=510, Rt=2.20 min

Example 199 {2-[3-(4-tert-Butyl-cyclohexylmethyl)-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(3,4-difluoro-phenyl)-3-(4-tert-butyl-cyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using 4-tert-butyl-cyclohexylmethyl-(3,4-difluorophenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

HPLC-MS: M/Z=498, Rt=2.59 min.

Example 200 {2-[3-Cyclopentylmethyl-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(2,3,4-trifluorophenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

HPLC-MS: M/Z=446, Rt=2.59 min.

Example 201 {2-[3-(3-Chloro-4-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3-chloro-4-fluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(3-chloro-4-fluoro-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.62 (dd, 1H), 7.45 (t, 1H), 7.38 (s,1H), 7.32-7.37 (m, 1H), 3.68 (d, 1H), 3.49 (s, 1H), 1.93 (ddd, 1H),1.52-1.64 (m, 3H), 1.40-1.51 (m, 1H), 1.11-1.21 (m, 1H)

HPLC-MS: M/Z=444, Rt=2.28 min.

Example 202 {2-[3-Cyclopentylmethyl-3-(2,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(2,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclopentylmethyl-(2,4-difluorophenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.45-7.52 (m, 1H), 7.34-7.41 (m, 1H),7.14 (t, 1H), 3.62 (d, 1H), 3.50 (s, 1H), 1.86-1.97 (m, 1H), 1.52-1.63(m, 3H), 1.40-1.51 (m, 1H), 1.12-1.22 (m, 1H)HPLC-MS: M/Z=367, Rt=2.14min

Example 203 {2-[3-Cyclopentylmethyl-3-(2,3-dichloro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(2,3-dichloro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclopentylmethyl-(2,3-dichlorophenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.65 (dd, 1H), 7.40-7.46 (m, 1H), 7.36(s, 1H), 3.80-3.90 (m, 1H), 3.50 (s, 1H), 1.97 (ddd, 1H), 1.51-1.70 (m,3H), 1.41-1.51 (m, 1H), 1.12-1.27 (m, 1H)

HPLC-MS: M/Z=460, Rt=2.31 min.

Example 204 {2-[3-Cyclopentylmethyl-3-(3-fluoro-4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3-fluoro-4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(3-fluoro-4-methoxy-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.37 (s, 1H), 7.25 (dd, 1H), 7.19 (t,1H), 7.09 (dd, 1H), 3.87 (s, 3H), 3.63 (d, 1H), 3.49 (s, 1H), 1.87-1.97(m, 1H), 1.52-1.64 (m, 3H), 1.40-1.50 (m, 1H), 1.12-1.22 (m, 1H)

HPLC-MS: M/Z=304, Rt=2.11 min.

Example 205{2-[3-(3-Acetylamino-phenyl)-3-benzyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(3-acetylamino-phenyl)-3-benzyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using (3-acetylamino-phenyl)-benzylamine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 9.99 (s, 1H), 7.53 (d, 1H), 7.41 (s,1H), 7.39 (s, 1H), 7.26-7.33 (m, 1H), 7.20-7.26 (m, 3H), 6.88 (d, 1H),4.94 (s, 1H), 3.51 (s, 1H), 2.01 (s, 3H)

HPLC-MS: M/Z=457, Rt=1.64 min.

Example 206{2-[3-(3-Acetylamino-phenyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(3-acetylamino-phenyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using (3-acetylamino-phenyl)-phenethylamine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

HPLC-MS: M/Z=471, Rt=1.82 min.

Example 207{2-[3-(2-Cyclopentylethyl)-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclopentylethyl-(3,4-difluorophenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.43-7.54 (m, 1H), 7.38 (s, 1H),7.13-7.19 (m, 1H), 3.63-3.73 (m, 1H), 3.49 (s, 1H), 1.66-1.76 (m, 3H),1.51-1.56 (m, 1H), 1.43-1.49 (m, 3H), 0.99-1.09 (m, 1H)

HPLC-MS: M/Z=442, Rt=2.31 min.

Example 208 {2-[3-(3,4-Difluoro-phenyl)-3-(trans-4-methyl-cyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{{2-[3-(3,4-difluoro-phenyl)-3-(trans-4-methyl-cyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using trans-4-methyl-cyclohexylmethyl-(3,4-difluorophenyl)-amineand (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.45-7.55 (m, 1H), 7.39 (s, 1H),7.15-7.21 (m, 1H), 3.58 (d, 1H), 3.49 (s, 1H), 1.59-1.69 (m, 3H),1.18-1.39 (m, 1H), 0.86-0.98 (m, 1H), 0.73-0.84 (m, 3H)

HPLC-MS: M/Z=456, Rt=2.39 min

Example 209 {2-[3-(3-Acetylamino-4-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-(3-acetylamino-4-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using N-(3-amino-4-fluoro-phenyl)-acetamide,cyclopentanecarbaldehyde and (2-amino-thiazol-5-ylsulfanyl)acetic acidethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 9.85 (s, 1H), 7.90 (d, 1H), 7.37 (s,1H), 7.24-7.31 (m, 1H), 7.02-7.08 (m, 1H), 3.63 (d, 1H), 3.49 (s, 1H),2.09 (s, 3H), 1.96 (ddd, 1H), 1.52-1.65 (m, 3H), 1.40-1.51 (m, 1H),1.12-1.24 (m, 1H)

HPLC-MS: M/Z=467, Rt=1.74 min

Example 210{2-[3-Cyclopentylmethyl-3-(3-propionylamino-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3-propionylamino-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using N-(3-amino-phenyl)-propionamide, cyclopentanecarbaldehydeand (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 10.01 (s, 1H), 7.60 (d, 1H), 7.53 (s,1H), 7.37 (s, 1H), 7.33 (t, 1H), 6.96 (d, 1H), 3.66 (d, 1H), 3.50 (s,1H), 2.32 (q, 1H), 1.91-2.01 (m, 1H), 1.53-1.64 (m, 3H), 1.40-1.51 (m,1H), 1.14-1.24 (m, 1H), 1.07 (t, 3H)

HPLC-MS: M/Z=463, Rt=1.82 min.

Example 211 {2-[3-Cyclopentylmethyl-3-(3-isobutyrylamino-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3-isobutyrylamino-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using N-(3-Amino-phenyl)-isobutyramide, cyclopentanecarbaldehydeand (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) d ppm 9.96 (s, 1H), 7.62 (d, 1H), 7.54 (s,1H), 7.37 (s, 1H), 7.33 (t, 1H), 6.96 (d, 1H), 3.66 (d, 1H), 3.49 (s,1H), 2.54-2.62 (m, 1H), 1.91-2.03 (m, 1H), 1.53-1.64 (m, 3H), 1.40-1.50(m, 1H), 1.15-1.27 (m, 1H), 1.09 (d, 3H)

HPLC-MS: M/Z=477, Rt=1.92 min.

Example 212(2-{3-[3-(Cyclopentanecarbonyl-amino)-phenyl]-3-cyclopentylmethyl-ureido}-thiazol-5-ylsulfanyl)-aceticacid

The title compound was prepared via(2-{3-[3-(cyclopentanecarbonyl-amino)-phenyl]-3-cyclopentylmethyl-ureido}-thiazol-5-ylsulfanyl)-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclopentanecarboxylic acid (3-amino-phenyl)-amide,cyclopentanecarbaldehyde and (2-amino-thiazol-5-ylsulfanyl)acetic acidethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 10.00 (s, 1H), 7.62 (d, 1H), 7.54 (s,1H), 7.37 (s, 1H), 7.33 (t, 1H), 6.96 (d, 1H), 3.66 (d, 1H), 3.49 (s,1H), 2.77 (dq, 1H), 1.91-2.02 (m, 1H), 1.78-1.89 (m, 1H), 1.65-1.71 (m,3H), 1.53-1.62 (m, 3H), 1.40-1.49 (m, 1H), 1.14-1.25 (m, 1H)

HPLC-MS: M/Z=503, Rt=2.09 min

Example 213{2-[3-(trans-4-Methyl-cyclohexylmethyl)-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(trans-4-methyl-cyclohexylmethyl)-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]thiazol-4-yl}-aceticacid, usingtrans-4-methyl-cyclohexylmethyl-(2,3,4-trifluorophenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.31-7.43 (m, 3H), 3.55 (d, 1H), 3.50(s, 1H), 1.65 (t, 3H), 1.20-1.38 (m, 1H), 0.87-0.99 (m, 1H), 0.83 (d,3H), 0.74-0.86 (m, 1H)

HPLC-MS: M/Z=474, Rt=2.41 min.

Example 214{2-[3-Cyclohexylmethyl-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(cyclohexylmethyl)-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using (methyl-cyclohexylmethyl-(2,3,4-trifluorophenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.31-7.44 (m, 3H), 3.55 (d, 1H), 3.50(s, 1H), 1.56-1.70 (m, 3H), 1.34-1.47 (m, 1H), 1.06-1.20 (m, 3H),0.85-1.00 (m, 1H)

HPLC-MS: M/Z=460, Rt=2.32 min.

Example 215 {2-[3-Cyclopentylmethyl-3-(2,3-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-(cyclohexylmethyl)-3-(2,3-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using (methyl-cyclohexylmethyl-(2,3-difluorophenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.35-7.46 (m, 1H), 7.21-7.29 (m, 1H),3.68 (d, 1H), 3.50 (s, 1H), 1.89-2.00 (m, 1H), 1.52-1.63 (m, 3H),1.40-1.50 (m, 1H), 1.09-1.24 (m, 1H)

HPLC-MS: M/Z=427, Rt=2.07 min

Example 216 {2-[3-Cyclopentylmethyl-3-(4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-(cyclohexylmethyl)-3-(4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using (methyl-cyclohexylmethyl-(4-methoxy-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.36 (s, 1H), 7.22 (d, 1H), 6.98 (d,1H), 3.78 (s, 3H), 3.62 (d, 1H), 3.49 (s, 1H), 1.87-1.98 (m, 1H),1.52-1.64 (m, 3H), 1.39-1.50 (m, 1H), 1.13-1.24 (m, 1H)

HPLC-MS: M/Z=422, Rt=2.03 min.

Example 217 {2-[3-(3-Chloro-4-methoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-(cyclohexylmethyl)-3-(3-chloro-4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using (methyl-cyclohexylmethyl-(3-chloro-4-methoxy-phenyl)-amineand (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.41 (d, 1H), 7.37 (s, 1H), 7.25 (dd,1H), 7.17 (d, 1H), 3.88 (s, 3H), 3.63 (d, 1H), 3.49 (s, 1H), 1.87-1.98(m, 1H), 1.52-1.64 (m, 3H), 1.40-1.51 (m, 1H), 1.12-1.23 (m, 1H)

HPLC-MS: M/Z=456, Rt=2.16 min.

Example 218 {2-[3-Cyclopentylmethyl-3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using 2,2-difluoro-benzo[1,3]dioxol-5-yl-cyclohexylmethyl-amineand (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.50 (d, 1H), 7.44 (d, 1H), 7.38 (s,1H), 7.15 (dd, 1H), 3.66 (d, 1H), 3.49 (s, 1H), 1.89-1.99 (m, 1H),1.54-1.65 (m, 3H), 1.40-1.52 (m, 1H), 1.13-1.23 (m, 1H)

HPLC-MS: M/Z=472, Rt=2.24 min.

Example 219{2-[3-Cyclopentylmethyl-3-(3-methanesulfonylamino-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3-methanesulfonylamino-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using N-(3-Amino-phenyl)-methanesulfonamide,cyclopentanecarbaldehyde and (2-amino-thiazol-5-ylsulfanyl)acetic acidethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 9.84 (s, 1H), 7.35-7.41 (m, 1H),7.11-7.18 (m, 1H), 7.04 (d, 1H), 3.65 (d, 1H), 3.50 (s, 1H), 3.04 (s,3H), 1.91-2.02 (m, 1H), 1.52-1.64 (m, 3H), 1.39-1.50 (m, 1H), 1.13-1.24(m, 1H)

HPLC-MS: M/Z=485, Rt=1.78 min

Example 220 {2-[3-Cyclopentylmethyl-3-(2,4,6-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(2,4,6-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(2,4,6-trifluorophenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.31-7.41 (m, 3H), 3.35-3.61 (m, 3H),1.89-1.99 (m, 1H), 1.52-1.63 (m, 3H), 1.42-1.50 (m, 1H), 1.13-1.24 (m,1H)

HPLC-MS: M/Z=446, Rt=2.06 min

Example 221 {2-[3-(3-Chloro-2-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-(3-chloro-2-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(3-chloro-2-fluoro-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.53-7.62 (m, 1H), 7.35-7.45 (m, 1H),7.27 (t, 1H), 3.66 (d, 1H), 3.51 (s, 1H), 1.87-1.98 (m, 1H), 1.52-1.64(m, 3H), 1.42-1.50 (m, 1H), 1.12-1.23 (m, 1H)

HPLC-MS: M/Z=444, Rt=2.11 min

Example 222 {2-[3-Cyclopentylmethyl-3-(4-fluoro-3-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(4-fluoro-3-methoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(4-fluoro-3-methoxy-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) d ppm 7.38 (s, 1H), 7.24 (dd, 1H), 7.13 (dd,1H), 6.84-6.90 (m, 1H), 3.83 (s, 3H), 3.66 (d, 1H), 3.49 (s, 1H),1.90-2.01 (m, 1H), 1.54-1.65 (m, 3H), 1.40-1.51 (m, 1H), 1.13-1.24 (m,1H)

HPLC-MS: M/Z=440, Rt=2.02 min.

Example 223 {2-[3-Cyclopentylmethyl-3-(2,3-difluoro-4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(2,3-difluoro-4-methoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclopentylmethyl-(2,3-difluoro-4-methoxy-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.38 (s, 1H), 7.17-7.25 (m, 1H),7.02-7.10 (m, 1H), 3.91 (s, 3H), 3.61 (d, 1H), 3.50 (s, 1H), 1.88-1.98(m, 1H), 1.52-1.64 (m, 3H), 1.40-1.50 (m, 1H), 1.13-1.23 (m, 1H)

HPLC-MS: M/Z=458, Rt=2.07 min.

Example 224 {2-[3-Cyclopentylmethyl-3-(4-isopropoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-(4-isopropoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentyl methyl-(4-isopropoxy-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.36 (s, 1H), 7.19 (d, 1H), 6.95 (d,1H), 4.57-4.66 (m, 1H), 3.61 (d, 1H), 3.49 (s, 1H), 1.88-1.99 (m, 1H),1.51-1.65 (m, 3H), 1.39-1.50 (m, 1H), 1.29 (d, 3H), 1.13-1.24 (m, 1H)

HPLC-MS: M/Z=450, Rt=2.18 min.

Example 225 {2-[3-Cyclopentylmethyl-3-(3-fluoro-2-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-cyclopentylmethyl-3-(3-fluoro-2-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(3-fluoro-2-methyl-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.36 (s, 1H), 7.26-7.32 (m, 1H),7.14-7.22 (m, 1H), 7.10 (d, 1H), 3.74-3.86 (m, 1H), 3.49 (s, 2H),3.35-3.43 (m, 1H), 2.04 (d, 3H), 1.92-2.01 (m, 1H), 1.53-1.65 (m, 4H),1.41-1.51 (m, 2H), 1.14-1.26 (m, 2H)

HPLC-MS: M/Z=424, Rt=2.10 min.

Example 226 {2-[3-(3-Chloro-2-methoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-(3-chloro-2-methoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(3-chloro-2-methoxy-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.47-7.51 (m, 1H), 7.37 (s, 1H),7.23-7.27 (m, 1H), 7.16-7.20 (m, 1H), 3.74 (s, 3H), 3.50 (s, 2H),1.88-1.98 (m, 1H), 1.53-1.64 (m, 4H), 1.40-1.50 (m, 2H), 1.11-1.22 (m,2H)

HPLC-MS: M/Z=456, Rt=2.15 min.

Example 227 {2-[3-(3-Chloro-2-methyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-(3-chloro-2-methyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(3-chloro-2-methyl-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.45 (d, 1H), 7.36 (s, 1H), 7.26-7.31(m, 1H), 7.21-7.25 (m, 1H), 3.78-3.87 (m, 1H), 3.49 (s, 2H), 2.15 (s,3H), 1.91-2.01 (m, 1H), 1.53-1.65 (m, 4H), 1.41-1.51 (m, 2H), 1.14-1.26(m, 2H)

HPLC-MS: M/Z=439, Rt=2.23 min.

Example 228 {2-[3-Cyclopentylmethyl-3-(2-fluoro-3-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(2-fluoro-3-methyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(2-fluoro-3-methyl-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.37 (s, 1H), 7.24-7.30 (m, 1H), 7.21(t, 1H), 7.10-7.17 (m, 1H), 3.62 (d, 2H), 3.49 (s, 2H), 2.26 (d, 3H),1.88-1.98 (m, 1H), 1.51-1.63 (m, 4H), 1.40-1.49 (m, 2H), 1.13-1.24 (m,2H)

HPLC-MS: M/Z=424, Rt=2.12 min.

Example 229{2-[3-[2-(3,4-Difluoro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(3,4-difluoro-phenyl)-ethanol,4-trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-aceticacid ethyl ester.

¹H NMR (400 MHz, CDCl₃) 7.32 (s, 1H), 7.20-6.94 (m, 3H), 4.18-3.81 (m,1H), 3.52-3.41 (m, 2H), 3.39 (s, 2H), 2.93-2.78 (m, 2H), 1.87-1.68 (m,4H), 1.60-1.43 (m, 2H), 1.42-1.10 (m, 3H), 0.92 (d, 3H)

HPLC-MS: m/z=470

Example 230(2-{3-(4-trans-Methyl-cyclohexyl)-3-[2-(3,4,5-trifluoro-phenyl)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(3,4,5-trifluoro-phenyl)-ethanol,4-trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-aceticacid ethyl ester.

¹H NMR (400 MHz, CDCl₃) 7.30 (s, 1H), 7.03-6.85 (m, 2H), 4.14-3.77 (m,1H), 3.51-3.40 (m, 2H), 3.38 (s, 2H), 2.91-2.78 (m, 2H), 1.87-1.70 (m,4H), 1.60-1.43 (m, 2H), 1.42-1.10 (m, 3H), 0.92 (d, 3H)

HPLC-MS: m/z=488

Example 231(2-{3-(4-trans-Methyl-cyclohexyl)-3-[2-(2,4,5-trifluoro-phenyl)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(2,4,5-trifluoro-phenyl)-ethanol,4-trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-aceticacid ethyl ester.

HPLC-MS: m/z=488

Example 232(2-{3-(4-trans-Methyl-cyclohexyl)-3-[2-(2,3,4-trifluoro-phenyl)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared as described for the synthesis of{2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-(2,3,4-trifluoro-phenyl)-ethanol,4-trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-aceticacid ethyl ester.

HPLC-MS: m/z=488

Example 2332-{2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionicacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-chlorobenzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethylester

¹H NMR (400 MHz, DMSO-d₆) 7.53-7.49 (m, 1H), 7.45-7.41 (m, 1H), 7.38 (s,1H), 7.35-7.27 (m, 2H), 4.62 (s, 2H), 3.99-3.87 (m, 1H), 3.65-3.57 (m,2H), 3.56-3.49 (m, 2H), 1.73-1.63 (m, 2H), 1.63-1.48 (m, 4H), 1.39 (s,6H), 1.36-1.22 (m, 1H), 1.11-0.95 (m, 2H), 0.86 (d, 3H)

HPLC-MS: m/z=526

Example 2342-{2-[3-[2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionicacid

Prepared as described for the synthesis of{2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid using 2-fluoro-benzylbromide,(2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butylester and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethylester

¹H NMR (400 MHz, DMSO-d₆) 7.48-7.42 (m, 1H), 7.38 (s, 1H), 7.38-7.31 (m,1H), 7.21-7.13 (m, 2H), 4.58 (s, 2H), 3.98-3.86 (m, 1H), 3.60-3.54 (m,2H), 3.52-3.45 (m, 2H), 1.71-1.62 (m, 2H), 1.61-1.45 (m, 4H), 1.39 (s,6H), 1.36-1.23 (m, 1H), 1.10-0.95 (m, 2H), 0.86 (d, 3H)

HPLC-MS: m/z=510

Example 235 {2-[3-(2-Chloro-3-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-(2-chloro-3-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl esterin a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(2-chloro-3-fluoro-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.67 (dd, 1H), 7.46 (dd, 1H), 7.41 (d,1H), 7.37 (s, 1H), 3.63 (d, 2H), 3.50 (s, 2H), 1.87-1.97 (m, 1H),1.51-1.64 (m, 4H), 1.40-1.50 (m, 2H), 1.11-1.21 (m, 2H)

HPLC-MS: M/Z=425, Rt=1.82 min.

Example 236{2-[3-(3-Bromo-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(3-bromo-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl esterin a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclopentylmethyl-(3-bromo-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.55 (t, 1H), 7.50 (d, 1H), 7.30-7.39(m, 3H), 3.71 (d, 2H), 3.50 (s, 2H), 1.88-1.97 (m, 1H), 1.52-1.63 (m,4H), 1.40-1.49 (m, 2H), 1.12-1.20 (m, 2H)

HPLC-MS: M/Z=470, Rt=2.19 min.

Example 237 {2-[3-(4-Bromo-2-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-(4-bromo-2-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl esterin a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid,using cyclopentylmethyl-(4-bromo-2-fluoro-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.67 (dd, 1H), 7.46 (dd, 1H), 7.41 (d,1H), 7.37 (s, 1H), 3.63 (d, 2H), 3.50 (s, 2H), 1.87-1.97 (m, 1H),1.51-1.64 (m, 4H), 1.40-1.50 (m, 2H), 1.11-1.21 (m, 2H)

HPLC-MS: M/Z=488, Rt=2.25 min.

Example 238{2-[3-(2-Bromo-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(2-bromo-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl esterin a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclopentylmethyl-(2-bromo-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.71-7.76 (m, 1H), 7.40-7.48 (m, 2H),7.28-7.39 (m, 2H), 3.83-3.99 (m, 1H), 3.50 (s, 2H), 3.21-3.32 (m, 1H),1.93-2.04 (m, 1H), 1.52-1.71 (m, 4H), 1.41-1.51 (m, 2H), 1.11-1.28 (m,2H)

HPLC-MS: M/Z=470, Rt=2.18 min.

Example 239 {2-[3-Cyclopentylmethyl-3-(3-methoxy-5-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(3-methoxy-5-trifluoromethyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl esterin a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclopentylmethyl-(3-methoxy-5-trifluoromethyl-phenyl)-amineand (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.38 (s, 1H), 7.23 (br. s., 1H), 7.19(br. s., 2H), 3.85 (s, 3H), 3.74 (d, 2H), 3.50 (s, 2H), 1.89-1.99 (m,1H), 1.51-1.64 (m, 4H), 1.40-1.50 (m, 2H), 1.12-1.23 (m, 2H)

HPLC-MS: M/Z=490, Rt=2.39 min.

Example 240 {2-[3-(3-Acetyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid

The title compound was prepared via{2-[3-(3-acetyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl esterin a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-aceticacid, using cyclopentylmethyl-(3-acetyl-phenyl)-amine and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.86-7.92 (m, 1H), 7.84 (s, 1H),7.54-7.60 (m, 2H), 7.37 (s, 1H), 3.75 (d, 2H), 3.50 (s, 2H), 2.60 (s,3H), 1.88-2.00 (m, 1H), 1.51-1.64 (m, 4H), 1.38-1.50 (m, 2H), 1.12-1.24(m, 2H)

HPLC-MS: M/Z=434, Rt=2.08 min.

Example 241{2-[3-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared via{2-[3-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester in a similar manner as described for the synthesis of{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]thiazol-4-yl}-aceticacid, using1-[6-(cyclopentylmethyl-amino)-2,3-dihydro-indol-1-yl]-ethanone and(2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester

1H NMR (400 MHz, DMSO-d₆) ppm 7.92 (d, 1H), 7.35 (s, 1H), 7.26 (d, 1H),6.92 (dd, 1H), 4.14 (t, 2H), 3.63 (d, 2H), 3.49 (s, 2H), 3.16 (t, 2H),2.16 (s, 3H), 1.90-2.01 (m, 1H), 1.51-1.65 (m, 4H), 1.39-1.50 (m, 2H),1.14-1.24 (m, 2H).

HPLC-MS: M/Z=475, Rt=1.82 min.

Example 242 Further Compounds According to the Invention

A non-limiting example of further compounds according to the inventionare listed in Table 1. The preparation of the compounds Aa-Bx of generalformula (I) of the present invention may be performed according to oneor more of the described methods I-K as indicated for each compound inTable 1. Occasionally, the reaction may not be applicable as describedto each compound included within the disclosed scope of the invention.The compounds for which this occurs will be readily recognised by thoseskilled in the art. In these cases the reactions can be successfullyperformed by conventional modifications known to those skilled in theart, which is, by appropriate protection of interfering groups, bychanging to other conventional reagents, or by routine modification ofreaction conditions. Alternatively, other reactions disclosed herein orotherwise conventional will be applicable to the preparation of thecorresponding compounds of the invention. In all preparative methods,all starting materials are known or may be prepared by a person skilledin the art in analogy with the preparation of similar known compounds orby the General procedures A through K described herein.

TABLE 1 Com- pound Structure Name Method Aa

{2-[3-(2-Benzyloxy-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-aceticacid (I) Ab

{2-[3-[2-(2-Methyl-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-aceticacid (I) Ac

{2-[3-[2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-aceticacid (I) Ad

{2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-aceticacid (I) Ae

(2-{3-(4-Methyl-cyclohexyl)-3-[2-(2-trifluoromethyl-benzyloxy)-ethyl]-ureido}-thiazole-5-sulfonyl)-aceticacid (I) Af

{2-[3-[2-(4-Fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-aceticacid (I) Ag

{2-[3-[2-(2-Chloro-4-fluoro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-aceticacid (I) Ah

{2-[3-[2-(2,4-Difluoro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-aceticacid (I) Ai

2-{2-[3-(2-Benzyloxy-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2-methyl-propionicacid (I) Aj

2-Methyl-2-{2-[3-[2-(2-methyl-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-propionicacid (I) Ak

2-{2-[3-[2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2-methyl-propionicacid(I) Al

2-{2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2-methyl-propionicacid(I) Am

2-Methyl-2-(2-{3-(4-methyl-cyclohexyl)-3-[2-(2-trifluoromethyl-benzyloxy)-ethyl]-ureido}-thiazole-5-sulfonyl)-propionicacid (I) An

2-{2-[3-[2-(4-Fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2-methyl-propionicacid (I) Ao

2-{2-[3-[2-(2,4-Difluoro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2-methyl-propionicacid(I) Ap

{2-[3-(4-Methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazole-5-sulfonyl}-aceticacid (I) Aq

2-Methyl-2-{2-[3-(4-methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazole-5-sulfonyl}-propionicacid (I) Ar

{2-[3-(4-Methyl-cyclohexyl)-3-phenethyl-ureido]-thiazole-5-sulfonyl}-aceticacid (I) As

{2-[3-[2-(4-Methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-aceticacid (I) At

{2-[3-[2-(3-Fluoro-4-methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-aceticacid (I) Au

{2-[3-[2-(4-Ethoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-aceticacid (I) Av

2-Methyl-2-{2-[3-(4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazole-5-sulfonyl}-propionicacid (I) Aw

2-{2-[3-[2-(4-Methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2-methyl-propionicacid (I) Ax

2-{2-[3-[2-(3-Fluoro-4-methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2-methyl-propionicacid (I) Ay

2-{2-[3-[2-(3-Fluoro-4-methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2-methyl-propionicacid (I) Az

3-{2-[3-(2-Benzyloxy-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionicacid (J) Ba

3-{2-[3-[2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionicacid (J) Bb

2,2-Dimethyl-3-{2-[3-[2-(2-methyl-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid(J) Bc

3-{2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionicacid (J) Bd

2,2-Dimethyl-3-(2-{3-(4-methyl-cyclohexyl)-3-[2-(2-trifluoromethyl-benzyloxy)-ethyl]-ureido}-thiazol-5-ylsulfanyl)-propionicacid (J) Be

2,2-Dimethyl-3-{2-[3-(4-methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid (J) Bf

3-{2-[3-[3-(2-Chloro-phenoxy)-propyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionicacid (J) Bg

3-{2-[3-[3-(3-Chloro-phenoxy)-propyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionicacid (J) Bh

3-{2-[3-[3-(4-Chloro-phenoxy)-propyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionicacid (J) Bi

2,2-Dimethyl-3-{2-[3-(4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionicacid (J) Bj

3-{2-[3-[2-(4-Methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionicacid (J) Bk

3-{2-[3-[2-(4-Ethoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionicacid (J) Bl

3-{2-[3-[2-(3-Fluoro-4-methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionicacid (J) Bm

{2-[3-(2-Benzylsulfanyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid (K) Bn

2-{2-[3-(2-Benzylsulfanyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionicacid (K) Bo

{2-[3-(2-Benzylsulfanyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-aceticacid (K) + (I) Bp

2-{2-[3-(2-Benzylsulfanyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2-methyl-propionicacid (K) + (I) Bq

3-{2-[3-(2-Benzylsulfanyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionicacid (K) + (J) Br

3-{2-[3-(2-Benzylsulfanyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2,2-dimethyl-propionicacid (K) + (I) Bs

2,2-Dimethyl-3-{2-[3-(4-methyl-cyclohexyl)-3-(3-phenylsulfanyl-propyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid(K) + (J) Bt

2,2-Dimethyl-3-{2-[3-(4-methyl-cyclohexyl)-3-(3-phenylsulfanyl-propyl)-ureido]-thiazole-5-sulfonyl}-propionicacid(K) + (I) + (J) Bu

{2-[3-(4-Methyl-cyclohexyl)-3-(3-phenylsulfanyl-propyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid (K) Bv

2-Methyl-2-{2-[3-(4-methyl-cyclohexyl)-3-(3-phenylsulfanyl-propyl)-uredo]-thiazol-5-ylsulfanyl}-propionicacid(K) Bw

{2-[3-(4-Methyl-cyclohexyl)-3-(3-phenylsulfanyl-propyl)-ureido]-thiazole-5-sulfonyl}-aceticacid (K) + (I) Bx

2-Methyl-2-{2-[3-(4-methyl-cyclohexyl)-3-(3-phenylsulfanyl-propyl)-ureido]-thiazole-5-sulfonyl}-propionicacid(K) + (I)

1. A compound of formula (I)

wherein R¹ is C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, aryl, heteroaryl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₈-cycloalkyl-C₂₋₆-alkenyl,C₃₋₈-cycloalkyl-C₂₋₆-alkynyl, C₃₋₈-cycloalkenyl-C₁₋₆-alkyl,C₃₋₈-cycloalkenyl-C₂₋₆-alkenyl, C₃₋₈-cycloalkenyl-C₂₋₆-alkynyl,C₃₋₈-heterocyclyl-C₁₋₆-alkyl, C₃₋₈-heterocyclyl-C₂₋₆-alkenyl,C₃₋₈-heterocyclyl-C₂₋₆-alkynyl, C₃₋₈-heterocycloalkenyl-C₁₋₆-alkyl,C₃₋₈-heterocycloalkenyl-C₂₋₆-alkenyl,C₃₋₈-heterocycloalkenyl-C₂₋₆-alkynyl, aryl-C₁₋₆-alkyl,aryl-C₂₋₆-alkenyl, aryl-C₂₋₆-alkynyl, heteroaryl-C₁₋₆-alkyl,heteroaryl-C₂₋₆-alkenyl, heteroaryl-C₂₋₆-alkynyl, (fusedaryl-C₃₋₈-cycloalkyl)-C₁₋₆-alkyl, (fusedaryl-C₃₋₈-cycloalkyl)-C₂₋₆-alkenyl, (fusedaryl-C₃₋₈-cycloalkyl)-C₂₋₆-alkynyl, (fusedheteroaryl-C₃₋₈-cycloalkyl)-C₁₋₆-alkyl, (fusedheteroaryl-C₃₋₈-cycloalkyl)-C₂₋₆-alkenyl or (fusedheteroaryl-C₃₋₈-cycloalkyl-C₂₋₆-alkynyl) each of which is optionallysubstituted with one or more substituents R³, R⁴, R⁵ and R⁶; R² isC₁₋₈-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₈-alkyl,C₃₋₈-cycloalkenyl, C₃₋₈-heterocyclyl, C₃₋₈-heterocycloalkenyl, fusedaryl-C₃₋₈-cycloalkyl, or fused heteroaryl-C₃₋₈-cycloalkyl, each of whichis optionally substituted with one or more substituents R³⁰, R³¹, R³²and R³³; R³, R⁴, R⁵, R⁶, R³⁰, R³¹, R³² and R³³ are independentlyselected from the group consisting of halogen, nitro, cyano, hydroxy,oxo, carboxy, —CF₃; or —NR¹⁰R¹¹; or C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,C₃₋₈-cycloalkyl-C₃₋₆-alkenyl, aryl, aryl-C₁₋₆-alkyl, aryl-C₂₋₆-alkenyl,heteroaryl-C₁₋₆-alkyl, heteroaryl-C₂₋₆-alkenyl, heterocyclyl-C₁₋₆-alkyl,heterocyclyl-C₂₋₆-alkenyl, C₁₋₆-alkoxy, C₃₋₆-alkenyloxy,C₃₋₈-cycloalkoxy, C₃₋₆-cycloalkyl-C₁₋₆-alkoxy,C₃₋₈-cycloalkenyl-C₁₋₆-alkoxy, C₃₋₈-heterocyclyl-C₁₋₆-alkoxy, fusedaryl-C₃₋₈-cycloalkenyl-C₁₋₆-alkoxy, C₃₋₈-cycloalkyl-C₃₋₆-alkenyloxy,C₃₋₈-cycloalkenyl-C₃₋₆-alkenyloxy, C₃₋₈-heterocyclyl-C₃₋₆-alkenyloxy,fused C₃₋₈-cycloalkyl-aryloxy, fused heterocyclyl-aryloxy, fusedaryl-C₃₋₈-cycloalkenyl-C₃₋₆-alkenyloxy, aryl-C₁₋₆-alkoxy,aryl-C₃₋₆-alkenyloxy, heteroaryl, heteroaryl-C₁₋₆-alkoxy,heteroaryl-C₃₋₆-alkenyloxy, aryloxy, heteroaryloxy, C₁₋₆-alkylthio,C₃₋₆-alkenylthio, C₃₋₆-cycloalkyl-C₁₋₆-alkylthio,C₃₋₈-cycloalkenyl-C₁₋₆-alkylthio, C₃₋₈-heterocyclyl-C₁₋₆-alkylthio,fused aryl-C₃₋₈-cycloalkenyl-C₁₋₆-alkylthio,C₃₋₈-cycloalkyl-C₃₋₆-alkenylthio, C₃₋₈-cycloalkenyl-C₃₋₆-alkenylthio,C₃₋₈-heterocyclyl-C₃₋₆-alkenylthio, fusedaryl-C₃₋₈-cycloalkenyl-C₃₋₆-alkenylthio, aryl-C₁₋₆-alkylthio,aryl-C₃₋₆-alkenylthio, heteroaryl-C₁₋₆-alkylthio,heteroaryl-C₃₋₆-alkenylthio, arylthio, heteroarylthio amino-C₁₋₆-alkyl,C₁₋₆-alkylamino-C₁₋₆-alkyl, di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl,C₁₋₆-alkylsulfamoyl, di(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylsulfinamoyl ordi(C₁₋₆-alkyl)sulfinamoyl each of which is optionally substituted withone or more substituents independently selected from R¹²; or —C(O)—R²⁷,—S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, —S(O)₂—NR¹³R¹⁴, —C₁₋₆-alkyl-C(O)—NR¹³R¹⁴; ortwo substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹, R³² andR³³ attached to the same or adjacent atoms together may form a radical—O—(CH₂)₁₋₃—O—; R¹⁰ and R¹¹ independently represent hydrogen,C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl, —C(O)—C₃₋₈-cycloalkyl,carboxy-C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl-C(O)OH, —S(O)₂—C₁₋₆-alkyl, or aryl,each of which is optionally substituted with one or more halogens; R²⁷is C₁₋₆-alkyl, C₁₋₆-alkoxy, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₈-cycloalkyl-C₂₋₆-alkenyl, aryl,aryl-C₁₋₆-alkyl, aryloxy-C₁₋₆-alkyl, aryl-C₂₋₆-alkenyl, heteroaryl,C₃₋₈-heterocyclyl, heteroaryl-C₁₋₆-alkyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl,heteroaryloxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, carboxy-C₂₋₆-alkenyl,C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₂₋₆-alkenyl,C₁₋₆-alkylthio-C₁₋₆-alkyl, R¹⁰HN—C₁₋₆-alkyl, R¹⁰R¹¹—N—C₁₋₆-alkyl,R¹⁰R¹¹—N—C₂₋₆-alkenyl, R¹⁰R¹¹—N—S(O)₂—C₁₋₆-alkyl,R¹⁰R¹¹—N—C(O)—C₁₋₆-alkyl, C₁₋₆-alkyl-C(O)—NH—C₁₋₆-alkyl,aryl-C(O)—NH—C₁₋₆-alkyl, heteroaryl-C(O)—NH—C₁₋₆-alkyl,C₃₋₈-cycloalkyl-C(O)—NH—C₁₋₆-alkyl, C₁₋₆-alkyl-S(O)₂—NH—C₁₋₆-alkyl,aryl-S(O)₂—NH—C₁₋₆-alkyl, heteroaryl-S(O)₂—NH—C₁₋₆-alkyl, orC₃₋₈-cycloalkyl-S(O)₂—NH—C₁₋₆-alkyl, each of which is optionallysubstituted with one or more substituents independently selected fromR¹²; R¹² is halogen, cyano, hydroxy, —C(O)—O—C₁₋₆-alkyl, carboxy, —CF₃,C₁₋₆-alkyl, aryl, heteroaryl, C₁₋₆-alkoxy, C₂₋₆-alkenyloxy,C₃₋₈-cycloalkyloxy, C₃₋₈-cycloalkenyloxy, C₃₋₈-heterocyclyloxy, aryloxy,heteroaryloxy, aryl-C₁₋₆-alkoxy, aryl-C₁₋₆-alkenyloxy,heteroaryl-C₁₋₆-alkoxy, heteroaryl-C₁₋₆-alkenyloxy,C₃₋₈-cycloalkyl-C₁₋₆-alkoxy, C₃₋₈-cycloalkyl-C₁₋₆-alkenyloxy,C₃₋₈-heterocyclyl-C₁₋₆-alkoxy, C₃₋₈-heterocyclyl-C₁₋₆-alkenyloxy, fusedaryl-C₃₋₈-cycloalkyl-C₁₋₆-alkoxy, fusedaryl-C₃₋₈-cycloalkyl-C₁₋₆-alkenyloxy, C₁₋₆-alkylthio, C₂₋₆-alkenylthio,C₃₋₈-cycloalkylthio, C₃₋₈-cycloalkenylthio, C₃₋₈-heterocyclylthio,arylthio, heteroarylthio, aryl-C₁₋₆-alkylthio, aryl-C₁₋₆-alkenylthio,heteroaryl-C₁₋₆-alkylthio, heteroaryl-C₁₋₆-alkenylthio,C₃₋₈-cycloalkyl-C₁₋₆-alkylthio, C₃₋₈-cycloalkyl-C₁₋₆-alkenylthio,C₃₋₈-heterocyclyl-C₁₋₆-alkylthio, C₃₋₈-heterocyclyl-C₁₋₆-alkenylthio,fused aryl-C₃₋₈-cycloalkyl-C₁₋₆-alkylthio, fusedaryl-C₃₋₈-cycloalkyl-C₁₋₆-alkenylthio, —NR¹⁰R¹¹, —S(O)₂CH₃, —S(O)₂CF₃ or—S(O)₂NH₂ each of which is optionally substituted with one or moresubstituents independently selected from R³⁸; R¹³ and R¹⁴ areindependently selected from the group consisting of hydrogen,C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, aryl, or heteroaryl,each of which is optionally substituted with one or more substituentsindependently selected from R¹⁵; or R¹³ and R¹⁴ together with thenitrogen to which they are attached form a 3 to 8 membered heterocyclicring with the said nitrogen atom, the heterocyclic ring optionallycontaining one or two further heteroatoms selected from nitrogen, oxygenand sulphur; R¹⁵ is halogen, cyano, hydroxy, carboxy, —CF₃, C₁₋₆-alkyl,—S(O)₂CH₃, or —S(O)₂NH₂; R³⁸ is halogen or C₁₋₆-alkyl; A is heteroarylwhich is substituted with at least one substituent independentlyselected from R⁷, R⁸ and R⁹; wherein R⁷, R⁸ and R⁹ are independentlyselected from C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,C₃₋₆-cycloalkylthio, C₁₋₆-alkylamino, C₁₋₆-alkylsulfanyl,—C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl, —NH—C(O)—C₁₋₆-alkyl,—C₁₋₆-alkoxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-S—C₁₋₆-alkyl or hydroxy-C₁₋₆-alkyl,each of which is substituted with one or more substituents independentlyselected from R³⁴; or —C₁₋₆-alkyl-NR¹⁹R²⁰, —C₂₋₆-alkenyl-NR¹⁹R²⁰,—C₁₋₆-alkyl-S—R²¹, —C₁₋₆-alkyl-S(O)—R²¹, —C₁₋₆-alkyl-S(O)₂—R²¹,—S(O)₂—R²¹, —S(O)₂—N(R¹⁹)(C₁₋₆-alkyl)-C(O)—NR²²R²³ or —S(O)₂—NR¹⁹R²⁰,each of which is substituted with one or more substituents independentlyselected from R²⁵; or —C(O)NR²²R²³, —C₁₋₆-alkyl-C(O)NR²²R²³ each ofwhich is substituted with one or more substituents independentlyselected from R²⁵; or two of R⁷, R⁸ and R⁹ can be taken together to forma C₂₋₅-alkylene bridge; the C₂₋₅-alkylene bridge is optionallysubstituted with one or more substituents independently selected fromR¹⁶; or carboxy, nitro, hydroxy, —SCN; or C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₁₋₆-alkenyloxy, C₂₋₆-alkenylthio, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₆-alkyl, C₃₋₆-cycloalkoxy,C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, —C(O)—O—C₁₋₆-alkyl, formyl,—C(O)—C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl eachof which is optionally substituted with one or more substituentsindependently selected from R¹⁶; or heteroaryl, heteroaryl-C₁₋₆-alkyl,heteroaryl-C₁₋₆-alkoxy, heteroaryl-C₁₋₆-alkylthio,heteroaryl-thio-C₁₋₆-alkyl, heteroaryl-oxy-C₁₋₆-alkyl, heteroaryloxy,heteroarylthio, —C(O)-aryl, or —C(O)-heteroaryl, each of which isoptionally substituted on the aryl or heteroaryl part with one or moresubstituents independently selected from R¹⁷; or C₃₋₈-cycloalkyl,C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkylthio, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,C₃₋₈-cycloalkenyl-C₁₋₆-alkyl, C₃₋₆-cycloalkyl-C₁₋₆-alkoxy,C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, each of which is optionally substitutedon the cycloalkyl part with one or more substituents independentlyselected from R¹⁸; or C₃₋₈-heterocyclyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl,C₃₋₈-heterocyclyl-C₁₋₆-alkylthio, C₃₋₈-heterocyclylthio,C₃₋₈-heterocyclyl-amino-C₁₋₆-alkyl, or —C(O)—C₃₋₈-heterocyclyl, each ofwhich is optionally substituted with one or more substituentsindependently selected from R¹⁶; or —C₁₋₆-alkyl-NR³⁶R³⁷,—C₂₋₆-alkenyl-NR³⁶R³⁷ or —S(O)₂—NR³⁶R³⁷, each optionally substitutedwith one or more substituents independently selected from R²⁵; or—C(O)NR³⁶R³⁷, —C₁₋₆-alkyl-C(O)NR³⁶R³⁷—C₁₋₆-alkyl-NR²²R²³,—C₁₋₆-alkyl-NH—C(O)—C₁₋₆-alkyl-NR²²R²³, each optionally substituted withone or more substituents independently selected from R²⁶; If more thanone substituent R⁷, R⁸ and R⁹ is present on A that additional R⁷, R⁸ andR⁹ may be selected from halogen or C₁₋₆-alkyl; R¹⁶, R¹⁷, and R¹⁸ areindependently C₁₋₆-alkyl, halogen, nitro, cyano, hydroxy, carboxy, oxo,—CF₃, carboxy-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—NR¹⁹R²⁰,—C(O)—O—C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl-C(O)—C₁₋₆-alkyl, —NR¹⁹R²⁰,—NHS(O)₂C₁₋₆-alkyl, —NHS(O)₂CF₃, —C(O)NR¹⁹R²⁰, —S(O)₂C₁₋₆-alkyl,—S(O)₂CF₃, —S(O)₂CH₂CF₃ or —S(O)₂NR¹⁹R²⁰; R³⁴ is halogen, nitro, cyano,hydroxy, carboxy, —CF₃; or carboxy-C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl or—C(O)—C₁₋₆-alkyl-C(O)—C₁₋₆-alkyl each optionally substituted with one ormore halogens; R¹⁹ and R²⁰ independently represent hydrogen, C₁₋₆-alkyl,C₂₋₆-alkenyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, aryl, heteroaryl,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₈-heterocyclyl,aryl-C₁₋₆-alkyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-NR²²R²³, or—S(O)₂—C₁₋₆-alkyl, each of which is optionally substituted with one ormore substituents independently selected from R²⁴, or R¹⁹ and R²⁰together with the nitrogen to which they are attached form a 3 to 8membered heterocyclic ring with the said nitrogen atom, the heterocyclicring optionally containing one or two further heteroatoms selected fromnitrogen, oxygen and sulphur, the heterocyclic ring is optionallysubstituted with one or more substituents independently selected fromR²⁴; R²¹ is selected from C₁₋₆-alkyl, C₂₋₆-alkenyl, carboxy-C₁₋₆-alkyl,C₁₋₆-alkylamino-C₁₋₆-alkyl or hydroxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-NR²²R²³;or aryl, heteroaryl, aryl-C₁₋₆-alkyl, or heteroaryl-C₁₋₆-alkyl, whereinthe aryl or heteroaryl part is optionally substituted with one or moresubstituents independently selected from R²⁴; or C₃₋₈-cycloalkyl,C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,C₃₋₈-cycloalkenyl-C₁₋₆-alkyl; R²² and R²³ are independently selectedfrom hydrogen, C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl,—C₁₋₆-alkyl-S(O)₂—C₁₋₆-alkyl, —C₁₋₆-alkyl-S(O)₃H, C₃₋₈-cycloalkyl, aryl,or heteroaryl; or R²² and R²³ together with the nitrogen to which theyare attached form a 3 to 8 membered heterocyclic ring with the saidnitrogen atom, the heterocyclic ring optionally containing one or twofurther heteroatoms selected from nitrogen, oxygen and sulphur, theheterocyclic ring is optionally substituted with one or moresubstituents independently selected from R²⁴; R³⁶ and R³⁷ areindependently selected from carboxy-C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl,—C₁₋₆-alkyl-S(O)₂—C₁₋₆-alkyl, C₃₋₈-cycloalkyl, aryl, or heteroaryl; orR³⁶ and R³⁷ together with the nitrogen to which they are attached form a3 to 8 membered heterocyclic ring with the said nitrogen atom, theheterocyclic ring optionally containing one or two further heteroatomsselected from nitrogen, oxygen and sulphur, the heterocyclic ring isoptionally substituted with one or more substituents independentlyselected from R²⁴; R²⁴ is halogen, nitro, cyano, hydroxy, carboxy, oxo,—CF₃, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,—C(O)—C₁₋₆-alkyl, —C(O)—C₃₋₈-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)—C₃₋₈-heterocyclyl —C(O)—O—C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, aryl, heteroaryl, aryl-C₁₋₆-alkyl,heteroaryl-C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—C₃₋₈-heterocyclyl, —C(O)—O—C₁₋₆-alkyl-aryl,—NH—S(O)₂R²⁸, or —S(O)₂R²⁸, wherein each cyclic moiety is optionallysubstituted with one or more substituents independently selected fromR²⁹; R²⁵ and R²⁶ are independently C₁₋₆-alkyl, halogen, nitro, cyano,hydroxy, —C(O)—O—C₁₋₆-alkyl, carboxy, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, carboxy-C₃₋₈-cycloalkyl, —CF₃, —S(O)₂CH₃, or—S(O)₂NH₂; R²⁸ is C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, C₃₋₈-cycloalkyl, aryl, aryl-C₁₋₆-alkyl,heteroaryl optionally substituted with C₁₋₆-alkyl, —NH₂, or —N(CH₃)₂;R²⁹ is halogen, nitro, cyano, hydroxy, carboxy, oxo, —CF₃, C₁₋₆-alkyl,or C₁₋₆-alkoxy; R³⁵ is halogen, nitro, cyano, hydroxy,—C(O)—O—C₁₋₆-alkyl, carboxy, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, —CF₃, —S(O)₂CH₃, or —S(O)₂NH₂; as well as any salthereof with a pharmaceutically acceptable acid or base, or any opticalisomer or mixture of optical isomers, racemic mixture, or any tautomericforms thereof.
 2. A compound according to claim 1 wherein R¹ isC₁₋₈-alkyl, C₂₋₈-alkenyl, aryl, heteroaryl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,C₃₋₈-cycloalkyl-C₂₋₆-alkenyl, C₃₋₈-cycloalkenyl-C₁₋₆-alkyl,C₃₋₈-cycloalkenyl-C₂₋₆-alkenyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl,C₃₋₈-heterocyclyl-C₂₋₆-alkenyl, C₃₋₈-heterocycloalkenyl-C₁₋₆-alkyl,C₃₋₈-heterocycloalkenyl-C₂₋₆-alkenyl, aryl-C₁₋₆-alkyl, oraryl-C₂₋₆-alkenyl, each of which is optionally substituted with one ormore substituents R³, R⁴, R⁵ and R⁶.
 3. A compound according to claim 2wherein R¹ is C₁₋₈-alkyl, C₂₋₈-alkenyl, aryl, heteroaryl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₈-cycloalkyl-C₂₋₆-alkenyl,C₃₋₈-cycloalkenyl-C₁₋₆-alkyl, C₃₋₈-cycloalkenyl-C₂₋₆-alkenyl,aryl-C₁₋₆-alkyl, or aryl-C₂₋₆-alkenyl, each of which is optionallysubstituted with one or more substituents R³, R⁴, R⁵ and R⁶.
 4. Acompound according to claim 3 wherein R¹ is C₁₋₈-alkyl, C₂₋₈-alkenyl,aryl, heteroaryl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,C₃₋₈-cycloalkenyl-C₁₋₆-alkyl, or aryl-C₁₋₆-alkyl, each of which isoptionally substituted with one or more substituents R³, R⁴, R⁵ and R⁶.5. A compound according to claim 4 wherein R¹ is C₁₋₈-alkyl,C₂₋₈-alkenyl, phenyl, pyridinyl, benzo[1,3]dioxolyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₈-cycloalkenyl-C₁₋₆-alkyl, orphenyl-C₁₋₆-alkyl, each of which is optionally substituted with one ormore substituents R³, R⁴, R⁵ and R⁶.
 6. A compound according to claim 5wherein R¹ is methyl, ethyl, propyl, butyl, 3-methyl-butyl,2,2-dimethylpropyl, 1,3,-dimethylbutyl, isopropyl, 3-methyl-but-2-enylethenyl, propenyl, butenyl, cyclopropyl-methyl, cyclopropyl-ethyl,cyclopropyl-propyl, cyclobutyl-methyl, cyclobutyl-ethyl,cyclobutyl-propyl, cyclopentyl-methyl, cyclopentyl-ethyl,cyclopentyl-propyl, cyclohexyl-methyl, cyclohexyl-ethyl,cyclohexyl-propyl, cycloheptyl-methyl, cycloheptyl-ethyl,cycloheptyl-propyl, cyclohexenyl-methyl, cyclohexenyl-ethyl,cyclohexenyl-propyl, cycloheptenyl-methyl, cycloheptenyl-ethyl,cycloheptenyl-propyl, phenyl, pyridinyl, benzo[1,3]dioxolyl,dihydro-1H-indolyl, benzyl, phenethyl, phenyl-propyl,bicyclo[2.2.1]heptenyl-methyl or bicyclo[2.2.1]heptyl-methyl, each ofwhich is optionally substituted with one or more substituents R³, R⁴, R⁵and R⁶.
 7. A compound according to claim 6 wherein R¹ is methyl, ethyl,propyl, butyl, 3-methyl-butyl, 2,2-dimethylpropyl, 1,3,-dimethylbutyl,isopropyl, 3-methyl-but-2-enyl ethenyl, cyclohexyl-methyl,cyclohexyl-ethyl, cyclohexyl-propyl, cyclohexenyl-methyl,cyclohexenyl-ethyl, cyclohexenyl-propyl, cycloheptenyl-methyl,cycloheptenyl-ethyl, phenyl, pyridinyl, benzo[1,3]dioxolyl,dihydro-1H-indolyl, benzyl, phenethyl, phenylpropyl,bicyclo[2.2.1]heptenyl-methyl or bicyclo[2.2.1]heptyl-methyl, each ofwhich is optionally substituted with one or more substituents R³, R⁴, R⁵and R⁶.
 8. A compound according to claim 1 wherein R² is C₁₋₈-alkyl,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₈-alkyl or C₃₋₈-cycloalkenyl, eachof which is optionally substituted with one or more substituents R³⁰,R³¹, R³² and R³³.
 9. A compound according to claim 8 wherein R² isC₃₋₈-cycloalkyl or C₃₋₈-cycloalkyl-C₁₋₈-alkyl optionally substitutedwith one or more substituents R³⁰, R³¹, R³² and R³³.
 10. A compoundaccording to claim 9 wherein R² is C₃₋₈-cycloalkyl optionallysubstituted with one or more substituents R³⁰, R³¹, R³² and R³³.
 11. Acompound according to claim 8 wherein R² is methyl, ethyl, propyl,butyl, pentyl, hexyl, 3-methylbutyl, 3,3-dimethylbutyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, orcyclopentylethyl, each of which may optionally be substituted with R³⁰.12. A compound according to claim 11 wherein R² is cyclopentylmethyl orcyclohexylmethyl, each of which may optionally be substituted with R³⁰.13. A compound according to claim 11 wherein R² is cyclohexyl optionallysubstituted with R³⁰.
 14. A compound according to claim 1 which is


15. A compound according to claim 1 wherein R³, R⁴, R⁵, R⁶, R³⁰, R³¹,R³² and R³³ are independently selected from the group consisting ofhalogen, hydroxy, carboxy, —CF₃; or —NR¹⁰R¹¹; or C₁₋₆-alkyl,C₂₋₆-alkenyl, C₁₋₆-alkoxy, C₃₋₆-alkenyloxy, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkoxy, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, C₃₋₈-cycloalkenyl-C₁₋₆-alkoxy,phenyl-C₁₋₆-alkoxy, each of which is optionally substituted with one ormore substituents independently selected from R¹²; or Phenyl, phenoxy,benzyloxy, indanyloxy, benzo[1,3]dioxolyloxy, phenylthio, or benzylthio;or —C(O)—R²⁷, —S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, or —S(O)₂—NR¹³R¹⁴; or twosubstituents selected from R³, R⁴, R⁵ and R⁶ attached to the same oradjacent atoms together may form a radical —O—(CH2)1-3—O—.
 16. Acompound according to claim 15 wherein R³, R⁴, R⁵, R⁶, R³⁰, R³¹, R³² andR³³, are independently selected from the group consisting of halogen,—CF₃, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₁₋₆-alkoxy, phenyl, phenoxy, benzyloxy,indanyloxy, benzo[1,3]dioxolyloxy, phenylthio, benzylthio,phenyl-C₁₋₆-alkoxy, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkoxy, orC₃₋₆-cycloalkyl-C₁₋₆-alkoxy, each of which is optionally substitutedwith one or more substituents independently selected from R¹²; or—NR¹⁰R¹¹, —C(O)—R²⁷, —S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, or —S(O)₂—NR¹³R¹⁴.
 17. Acompound according to claim 16 wherein R³, R⁴, R⁵ and R⁶ areindependently selected from the group consisting of halogen, CF₃,C₁₋₆-alkyl, C₁₋₆-alkoxy, phenoxy, benzyloxy, phenylthio, benzylthio,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkoxy, or C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, eachof which is optionally substituted with one or more substituentsindependently selected from R¹²; or —NR¹⁰R¹¹, —C(O)—R²⁷, —S(O)₂—R²⁷,—C(O)—NR¹³R¹⁴, or —S(O)₂—NR¹³R¹⁴.
 18. A compound according to claim 16wherein R³⁰, R³¹, R³² and R³³ are independently selected from the groupconsisting of halogen, —CF₃, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₁₋₆-alkoxy,phenyl, phenoxy, benzyloxy, phenylthio, benzylthio, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkoxy, or C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, each of which isoptionally substituted with one or more substituents independentlyselected from R¹²; or —C(O)—R²⁷, —S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, or—S(O)₂—NR¹³R¹⁴.
 19. A compound according to claim 16 wherein R³, R⁴, R⁵,R⁶, R³⁰, R³¹, R³² and R³³ are independently selected from the groupconsisting of F, Cl, Br, —CF₃, methyl, ethyl, propyl, butyl, isopropyl,tert-butyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, propoxy, butoxy,isopropoxy, isobutoxy, tert-butoxy, cyclohexyloxy, phenoxy, benzyloxy,indanyloxy, benzo[1,3]dioxolyloxy, cyclopropyl-methoxy,cyclopropyl-ethoxy, cyclopropyl-propoxy, cyclobutyl-methoxy,cyclobutyl-ethoxy, cyclobutyl-propoxy, cyclopentyl-methoxy,cyclopentyl-ethoxy, cyclopentyl-propoxy, cyclohexyl-methoxy,cyclohexyl-ethoxy, cyclohexyl-propoxy, cycloheptyl-methoxy,cycloheptyl-ethoxy, cycloheptyl-propoxy, phenylethoxy, phenylthio orbenzylthio, each of which is optionally substituted with one or moresubstituents independently selected from R¹²; or —NR¹⁰R¹¹, —C(O)—R¹⁷,—S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, or —S(O)₂—NR¹³R¹⁴.
 20. A compound accordingto claim 19 wherein R³, R⁴, R⁵ and R⁶ are independently selected fromthe group consisting of F, Cl, Br, —CF₃, methyl, ethyl, propyl,isopropyl, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tert-butoxy,cyclohexyloxy, phenoxy, benzyloxy, indanyloxy, benzo[1,3]dioxolyloxy,phenylethoxy, phenylthio or benzylthio, each of which is optionallysubstituted with one or more substituents independently selected fromR¹²; or —NR¹⁰R¹¹, —C(O)—R²⁷, —S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, or—S(O)₂—NR¹³R¹⁴.
 21. A compound according to claim 19 wherein R³¹, R³²and R³³ are independently selected from the group consisting of methyl,ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, propoxy, butoxy,tert-butoxy, benzyloxy or cyclopropyl-methoxy, each of which isoptionally substituted with one or more substituents independentlyselected from R¹².
 22. A compound according to claim 1 wherein R¹⁰ andR¹¹ independently represent hydrogen, C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, C(O)—C₃₋₈-cycloalkyl, or S(O)₂—C₁₋₆-alkyl.
 23. Acompound according to claim 22 wherein R¹⁰ and R¹¹ independentlyrepresent hydrogen, —C(O)—C₁₋₆-alkyl, —C(O)—C₃₋₈-cycloalkyl, orS(O)₂—C₁₋₆-alkyl.
 24. A compound according to claim 22 wherein R¹⁰ andR¹¹ independently represent hydrogen, methyl, ethyl, propyl, butyl,—C(O)-methyl, —C(O)-ethyl, —C(O)-propyl, —C(O)-isopropyl, —C(O)-butyl,—C(O)-cyclopentyl, —S(O)₂-methyl, carboxy-ethyl, carboxy-propyl orcarboxy-butyl.
 25. A compound according to claim 1 wherein R²⁷ isC₁₋₆-alkyl, C₁₋₆-alkoxy, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl, aryl-C₂₋₆-alkenyl,heteroaryl, heteroaryl-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkylthio-C₁₋₆-alkyl, R¹⁰HN—C₁₋₆-alkyl,R¹⁰R¹¹N—C₁₋₆-alkyl, R¹⁰R¹¹N—S(O)₂—C₁₋₆-alkyl, orR¹⁰R¹¹N—C(O)—C₁₋₆-alkyl, each of which is optionally substituted withone or more substituents independently selected from R¹².
 26. A compoundaccording to claim 25 wherein R²⁷ is C₁₋₆-alkyl, C₁₋₆-alkoxy,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl-C₂₋₆-alkenyl, aryl,heteroaryl, aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,C₁₋₆-alkoxy-C₁₋₆-alkyl, R¹⁰HN—C₁₋₆-alkyl, R¹⁰R¹¹N—C₁₋₆-alkyl,R¹⁰R¹¹N—S(O)₂—C₁₋₆-alkyl, or R¹⁰R¹¹N—C(O)—C₁₋₆-alkyl, each of which isoptionally substituted with one or more substituents independentlyselected from R¹².
 27. A compound according to claim 26 wherein R²⁷ isC₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,aryl, heteroaryl-C₁₋₆-alkyl, aryl-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, or heteroaryl, each of which is optionallysubstituted with one or more substituents independently selected fromR¹².
 28. A compound according to claim 27 wherein R²⁷ is methyl, ethyl,propyl, n-butyl, isobutyl, 2,2,2-trifluoroethyl, cyclopropyl,cyclopentyl, cyclopropylmethyl, phenyl, pyridyl, thiophene, imidazole,or thiazole, each of which is optionally substituted with one or moresubstituents independently selected from R¹².
 29. A compound accordingto claim 28 wherein R²⁷ is methyl, ethyl, propyl, n-butyl, isobutyl,2,2,2-trifluoroethyl, cyclopropyl, cyclopentyl, cyclopropylmethyl,phenyl, pyridyl, thiophene, imidazole, or thiazole.
 30. A compoundaccording to claim 29 wherein R²⁷ is methyl, ethyl, or propyl.
 31. Acompound according to claim 1 wherein R¹² is halogen, —CF₃, —CN,C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, C₂₋₆-alkenyloxy,C₃₋₈-cycloalkyloxy, C₃₋₈-cycloalkenyloxy, aryloxy, aryl-C₁₋₆-alkoxy,aryl-C₁₋₆-alkenyloxy, C₃₋₈-cycloalkyl-C₁₋₆-alkoxy,C₃₋₈-cycloalkyl-C₁₋₆-alkenyloxy, C₃₋₈-heterocyclyl-C₁₋₆-alkoxy, orC₃₋₈-heterocyclyl-C₁₋₆-alkenyloxy, each of which is optionallysubstituted with one or more substituents independently selected fromR³⁸; or NR¹⁰R¹¹, or —S(O)₂—C₁₋₆-alkyl.
 32. A compound according to claim31 wherein R¹² is halogen, —CF₃, —CN, C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, C₃₋₈-cycloalkyloxy, aryloxy, aryl-C₁₋₆-alkoxy,C₃₋₈-cycloalkyl-C₁₋₆-alkoxy, or C₃₋₈-heterocyclyl-C₁₋₆-alkoxy, each ofwhich is optionally substituted with one or more substituentsindependently selected from R³⁸; or NR¹⁰R¹¹, or —S(O)₂—C₁₋₆-alkyl.
 33. Acompound according to claim 32 wherein R¹² is F, Cl, Br, —CF₃, —CN,methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, methoxy,methylthio, ethoxy, propoxy, butoxy, phenoxy, benzyloxy,cyclopropyl-methoxy, cyclopropyl-ethoxy, cyclobutyl-methoxy,cyclobutyl-ethoxy, cyclopentyl-methoxy, cyclopentyl-ethoxy,cyclohexyl-methoxy, cyclohexyl-ethoxy, —NHC(O)CH₃, or —S(O)₂—CH₃.
 34. Acompound according to claim 33 wherein R¹² is F, Cl, Br, —CF₃, —CN,methyl, ethyl, isopropyl, tert-butyl, methoxy, methylthio, ethoxy,cyclopropyl-methoxy, —NHC(O)CH₃, or —S(O)₂—CH₃.
 35. A compound accordingto claim 1 wherein R¹³ and R¹⁴ are independently selected from hydrogenand C₁₋₆-alkyl; or R¹³ and R¹⁴ together with the nitrogen to which theyare attached form a 3 to 8 membered heterocyclic ring with the saidnitrogen atom.
 36. A compound according to claim 1 wherein R¹⁵ isselected from F, Cl, Br, hydroxy, carboxy, —CF₃, or C₁₋₆-alkyl.
 37. Acompound according to claim 1 wherein R³⁸ is F, Cl, Br, methyl or ethyl.38. A compound according to claim 1 wherein A is


39. A compound according to claim 38 wherein A is


40. A compound according to claim 39 wherein A is


41. A compound according to claim 1 wherein A is substituted with atleast one substituent R⁷, R⁸ or R⁹ independently selected fromC₁₋₆-alkyl, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio, each of which issubstituted with one or more substituents independently selected fromR³⁴; or —C₁₋₆-alkyl-NR¹⁹R²⁰—S(O)₂—R²¹, —S(O)₂—NR¹⁹R²⁰, or—S(O)₂—N(R¹⁹)(C₁₋₆-alkyl)-C(O)—NR²²R²³, each of which is substitutedwith one or more substituents independently selected from R²⁵; or—C(O)—O—C₁₋₆-alkyl, C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, orcarboxy-C₁₋₆-alkyl, each of which is optionally substituted with one ormore substituents independently selected from R¹⁶; or C₃₋₈-cycloalkyl orC₃₋₈-cycloalkylthio, each of which is optionally substituted on thecycloalkyl part with one or more substituents independently selectedfrom R¹⁸; or —C₁₋₆-alkyl-NR³⁶R³⁷, or —S(O)₂—NR³⁶R³⁷, each optionallysubstituted with one or more substituents independently selected fromR²⁵; or —C₁₋₆-alkyl-C(O)NR³⁶R³⁷, or—C₁₋₆-alkyl-NH—C(O)—C₁₋₆-alkyl-NR²²R²³, each optionally substituted withone or more substituents independently selected from R²⁶.
 42. A compoundaccording to claim 41 wherein A is substituted with at least onesubstituent R⁷, R⁸ or R⁹ independently selected from C₁₋₆-alkylthiosubstituted with one or more substituents independently selected fromR³⁴; or —S(O)₂—R²¹, —S(O)₂—NR¹⁹R²⁰, or—S(O)₂—N(R¹⁹)(C₁₋₆-alkyl)-C(O)—NR²²R²³; or —C(O)—O—C₁₋₆-alkyl, which isoptionally substituted with one or more substituents independentlyselected from R¹⁶.
 43. A compound according to claim 42 wherein A issubstituted with at least one substituent R⁷, R⁸ or R⁹ independentlyselected from methylthio, ethylthio, propylthio, isopropylthio,butylthio or 2-methylpropylthio, each of which is substituted with oneor more substituents independently selected from R³⁴; or —S(O)₂—R²¹,—S(O)₂—NR¹⁹R²⁰, or —S(O)₂—N(R¹⁹)—CH₂—C(O)—NR²²R²³; or —C(O)—O—CH₂CH₃.44. A compound according to claim 43 wherein A is substituted with atleast one substituent R⁷, R⁸ or R⁹ independently selected frommethylthio, isopropylthio, ethylthio, or 2-methylpropylthio each ofwhich is substituted with one or more substituents independentlyselected from R³⁴.
 45. A compound according to claim 43 wherein R⁷, R⁸or R⁹ are independently selected from —S(O)₂—R²¹.
 46. A compoundaccording to claim 1 wherein if more than one substituent R⁷, R⁸ and R⁹is present on A that additional R⁷, R⁸ and R⁹ may be selected frommethyl, ethyl, propyl, butyl, Cl, F, or Br.
 47. A compound according toclaim 1 wherein R¹⁶, R¹⁷, and R¹⁸ are independently halogen, carboxy, orcarboxy-C₁₋₆-alkyl.
 48. A compound according to claim 1 wherein R³⁴ iscarboxy, carboxy-C₁₋₆-alkyl, or —C(O)—O—C₁₋₆-alkyl.
 49. A compoundaccording to claim 48 wherein R³⁴ is carboxy.
 50. A compound accordingto claim 1 wherein R¹⁹ and R²⁰ independently represent hydrogen,C₁₋₆-alkyl or carboxy-C₁₋₆-alkyl, or R¹⁹ and R²⁰ together with thenitrogen to which they are attached form a 3 to 8 membered heterocyclicring with the said nitrogen atom, the heterocyclic ring optionallycontaining one or two further heteroatoms selected from nitrogen, oxygenand sulphur, the heterocyclic ring is optionally substituted with one ormore substituents independently selected from R²⁴.
 51. A compoundaccording to claim 1 wherein R²¹ is selected from C₁₋₆-alkyl orcarboxy-C₁₋₆-alkyl.
 52. A compound according to claim 1 wherein R²² andR²³ are independently selected from C₁₋₆-alkyl.
 53. A compound accordingto claim 1 wherein R³⁶ and R³⁷ are independently selected fromcarboxy-C₁₋₆-alkyl.
 54. A compound according to claim 1 wherein R²⁴ iscarboxy or carboxy-C₁₋₆-alkyl.
 55. A compound according to claim 1wherein R²⁵ and R²⁶ are independently selected from carboxy orcarboxy-C₁₋₆-alkyl.
 56. A compound according to claim 1 wherein R²⁸ isC₁₋₆-alkyl, carboxy-C₃₋₈-cycloalkyl or carboxy-C₁₋₆-alkyl.
 57. Acompound according to claim 1 wherein R²⁹ is F, Cl, Br or carboxy.
 58. Acompound according to claim 1 wherein R³⁵ is F, Cl, Br or carboxy.